Nucleic acids encoding immunoglobulin domains

ABSTRACT

Monoclonal antibodies directed against coagulation factors and their use in inhibiting thrombosis are disclosed.

This application claims the benefit of U.S. Provisional application Ser.No. 60/010,108, filed Jan. 17, 1996, now abandoned, and U.S. Provisionalapplication Ser. No. 60/029,119, filed Oct. 24, 1996, now abandoned.

FIELD OF THE INVENTION

This invention relates to monoclonal antibodies (mAbs) that hind to ahuman coagulation factor or cofactor and their use as self-limitinginhibitors of thrombosis.

BACKGROUND OF THE INVENTION

Under normal circumstances, an injury, be it minor or major, to vascularendothelial cells lining a blood vessel triggers a hemostatic responsethrough a sequence of events commonly referred to as the coagulation"cascade." The cascade culminates in the conversion of solublefibrinogen to insoluble fibrin which, together with platelets, forms alocalized clot or thrombus which prevents extravasation of bloodcomponents. Wound healing can then occur followed by clot dissolutionand restoration of blood vessel integrity and flow.

The events which occur between injury and clot formation are a carefullyregulated and linked series of reactions. In brief, a number of plasmacoagulation proteins in inactive proenzyme forms and cofactors circulatein the blood. Active enzyme complexes are assembled at an injury siteand are sequentially activated to serine proteases, with each successiveserine protease catalyzing the subsequent proenzyme to proteaseactivation. This enzymatic cascade results in each step magnifying theeffect of the succeeding step. For an overview of the coagulationcascade see the first chapter of "Thombosis and Hemorrhage", J. Loscalzoand A. Schafer, eds., Blackwell Scientific Publications, Oxford, England(1994).

While efficient clotting limits the loss of blood at an injury site,inappropriate formation of thrombi in veins or arteries is a commoncause of disability and death. Abnormal clotting activity can result inand/or from pathologies or treatments such as myocardial infarction,unstable angina, atrial fibrillation, stroke, renal damage, percutaneoustranslumenal coronary angioplasty, disseminated intravascularcoagulation, sepsis, pulmonary embolism and deep vein thrombosis. Theformation of clots on foreign surfaces of artificial organs, shunts andprostheses such as artificial heart valves is also problematic.

Approved anticoagulant agents currently used in treatment of thesepathologies and other thrombotic and embolic disorders include thesulfated heteropolysaccharides heparin and low molecular weight (LMW)heparin. These agents are administered parenterally and can cause rapidand complete inhibition of clotting by activation of the thrombininhibitor, antithrombin III and inactivation of all of the clottingfactors.

However, due to their potency, heparin and LMW heparin suffer drawbacks.Uncontrolled bleeding as a result of the simple stresses of motion andaccompanying contacts with physical objects or at surgical sites is themajor complication and is observed in 1 to 7% of patients receivingcontinuous infusion and in 8 to 14% of patients given intermittent bolusdoses. To minimize this risk, samples are continuously drawn to enableex vivo clotting times to be continuously monitored, which contributessubstantially to the cost of therapy and the patient's inconvenience.

Further, the therapeutic target range to achieve the desired level ofefficacy without placing the patient at risk for bleeding is narrow. Thetherapeutic range is approximately 1 to less than 3 ug heparin/ml plasmawhich results in activated partial thromboplastin time (aPTT) assaytimes of about 35 to about 100 seconds. Increasing the heparinconcentration to 3 ug/ml exceeds the target range and at concentrationsgreater than 4 ug/ml, clotting activity is not detectable. Thus, greatcare must be taken to keep the patient's plasma concentrations withinthe therapeutic range.

Another approved anticoagulant with slower and longer lasting effect iswarfarin, a coumarin derivative. Warfarin acts by competing with VitaminK dependent post-translational modification of prothrombin and otherVitamin K-dependent clotting factors.

The general pattern of anticoagulant action,in which blood is renderednon-clottable at concentrations only slightly higher than thetherapeutic range is seen for warfarin as well as for heparin and LMWheparin. Clearly, a need exists for an anticoagulant agent which isefficacious in controlling thrombotic and embolic disorders yet does notcause uncontrolled bleeding or its possibility.

SUMMARY OF THE INVENTION

Accordingly, one aspect of the present invention is a method forinhibiting thrombosis in an animal comprising administering an effectivedose of an anti-coagulation factor monoclonal antibody havingself-limiting neutralizing activity.

Another aspect of the invention is an anti-coagulation factor monoclonalantibody having self-limiting neutralizing activy against thecoagulation factor.

Another aspect of the invention is a monoclonal antibody having theidentifying characteristics of SB 249413, SB 249415, SB 249416, SB249417, SB 257731, SB 257732, 9E4(2)F4 or 11G4(1)B9.

Another aspect of the invention is a hybridoma cell line having theidentifying characteristics of 9E4(2)F4 or 11G4(1)B9.

Another aspect of the invention is a neutralizing Fab fragment orF(ab')₂ fragment thereof, produced by deleting the Fc region of themonoclonal antibodies of the invention.

Another aspect of the invention is a neutralizing Fab fragment orF(ab')₂ fragment thereof, produced by chain shuffling whereby the Fdheavy chain of the monoclonal antibodies of the invention is expressedin a murine light chain filamentous phage Fab display library.

Another aspect of the invention is a neutralizing Fab fragment orF(ab')₂ fragment thereof, produced by chain shuffling whereby the lightchain of the monoclonal antibodies of the invention is expressed in amurine heavy chain filamentous phage Fab display library.

Another aspect of the invention is an immunoglobulin heavy chaincomplementarity determining region having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 8, 9 and 10.

Another aspect of the invention is an immunoglobulin light chaincomplementarity determining region having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 12, 13 and 14.

Another aspect of the invention is an altered antibody comprising aheavy chain and a light chain, wherein the framework regions of saidheavy and light chains are derived from at least one selected antibodyand the amino acid sequences of the complementarity determining regionsof each said chain are derived from an anti-coagulation factormonoclonal antibody having self-limiting neutralizing activity againstthe coagulation factor.

Another aspect of the invention is a chimeric antibody comprising aheavy chain and a light chain, said antibody characterized by inhibitingthe function of intrinsic or common pathway coagulation factors in aself-limiting manner, wherein thrombosis is inhibited and limitedmodulation of coagulation is produced, wherein the constant regions ofsaid heavy and light chains are derived from at least one selectedantibody and the amino acid sequences of the variable regions of eachsaid chain are derived from an anti-coagulation factor monoclonalantibody having self-limiting neutralizing activity against thecoagulation factor.

Yet another aspect of the invention is a pharmaceutical compositioncomprising the humanized antibodies or chimeric antibody of theinvention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of experimental results demonstrating the titration ofnormal human plasma with the murine anti-Factor IX mAbs BC1 and BC2.

FIG. 2 is a graph of experimental results demonstrating the titration ofnormal human plasma with the murine anti-Factor IX mAbs 9E4(2)F4 and11G4(1)B9.

FIG. 3 is a graph of experimental results demonstrating the titration ofnormal human plasma with the murine anti-Factor X mAbs HFXHC and HFXLCand the murine anti-Factor XI mAb HFXI.

FIG. 4 is a histogram of experimental results demonstrating the effectof heparin, acetylsalicylic acid and murine Factor IX mabs on activatedpartial thromboplastin time (APTT) at 60 minutes in a rat carotidthrombosis model.

FIG. 5 is a histogram of experimental results demonstrating the effectof heparin, acetylsalicylic acid and murine Factor IX mabs onprothrombin time at 60 minutes in a rat carotid thrombosis model.

FIG. 6 is a histogram of experimental results demonstrating the effectof heparin, acetylsalicylic acid and murine Factor IX mabs on occlusionof carotid artery flow in a rat carotid thrombosis model.

FIG. 7 is a histogram of experimental results demonstrating the effectof heparin, acetylsalicylic acid and murine Factor IX mabs on thrombusweight in a rat carotid thrombosis model.

FIG. 8 is a histogram of experimental results demonstrating the effectof heparin, the murine Factor IX mab BC2, a chimeric Factor IX mab andhumanized factor IX mAbs on aPTT at 60 minutes in a rat carotidthrombosis model.

FIG. 9 is a histogram of experimental results demonstrating the effectof heparin, the murine Factor IX mab BC2, a chimeric Factor IX mab andhumanized factor IX mAbs on thrombus weight in a rat carotid thrombosismodel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a variety of antibodies, alteredantibodies and fragments thereof directed against coagulation factors,which are characterized by self-limiting neutralizing activity.Preferably, the coagulation factor is from the intrinsic or commoncoagulation pathway. Most preferably, the anti-coagulation factorantibodies are anti-Factor IX, anti-Factor IXa, anti-Factor X,anti-Factor Xa, anti-Factor XI, anti-Factor XIa, anti-Factor VIII,anti-Factor VIIIa, anti-Factor V, anti-Factor Va, anti-Factor VII,anti-Factor VIIa or anti-thrombin. Particularly preferred areanti-Factor IX antibodies. Exemplary anti-coagulation factor antibodiesare the humanized monoclonal antibodies SB 249413, SB 249415, SB 249416,SB 249417, SB 257731 and SB 257732 directed against human Factor IX, thechimeric monoclonal antibody chαFIX directed against human Factor IX,the murine monoclonal antibodies BC1, BC2, 9E4(2)F4 and 11G4(1)B9 whichare directed against human Factor IX and/or Factor IXa or the murinemonoclonal antibodies HFXLC and HFXI which are directed against humanFactors X and XI, respectively. Particularly preferred is the anti-humanFactor IX monoclonal antibody SB 249417.

The antibodies of the present invention can be prepared by conventionalhybridoma techniques, phage display combinatorial libraries,immunoglobulin chain shuffling and humanization techniques to generatenovel self-limiting neutralizing antibodies. Also included are fullyhuman mAbs having self-limiting neutralizing activity. These productsare useful in therapeutic and pharmaceutical compositions for thromboticand embolic disorders associated with myocardial infarction, unstableangina, atrial fibrillation, stroke, renal damage, pulmonary embolism,deep vein thrombosis, percutaneous translumenal coronary angioplasty,disseminated intravascular coagulation, sepsis, artificial organs,shunts or prostheses.

As used herein, the term "self-limiting neutralizing activity" refers tothe activity of an antibody that binds to a human coagulation factor,preferably from the intrinsic and common pathways, including FactorIX/IXa, X/Xa, XI/XIa, VIII/VIIIa and V/Va, VII/VIIa and thrombin andinhibits thrombosis in a manner such that limited modulation ofcoagulation is produced. "Limited modulation of coagulation" is definedas an increase in clotting time, as measured by prolongation of theactivated partial thromboplastin time (aPTT), where plasma remainsclottable with aPTT reaching a maximal value despite increasingconcentrations of monoclonal antibody. This limited modulation ofcoagulation is in contrast to plasma being rendered unclottable andexhibiting an infinite aPTT in the presence of increasing concentrationsof heparin. Preferably, the maximal aPTT value of the methods of theinvention are within the heparin therapeutic range. Most preferably,maximal aPTT is within the range of about 35 seconds to about 100seconds which corresponds to about 1.5 times to about 3.5 times thenormal control aPTT value. In one embodiment of the invention, aPTT isprolonged without significant prolongation of prothrombin time (PT).

"Altered antibody" refers to a protein encoded by an alteredimmunoglobulin coding region, which may be obtained by expression in aselected host cell. Such altered antibodies are engineered antibodies(e.g., chimeric or humanized antibodies) or antibody fragments lackingall or part of an immunoglobulin constant region, e.g., Fv, Fab, Fab' orF(ab')₂ and the like.

"Altered immunoglobulin coding region" refers to a nucleic acid sequenceencoding an altered antibody of the invention. When the altered antibodyis a CDR-grafted or humanized antibody, the sequences that encode thecomplementarity determining regions (CDRs) from a non-humanimmunoglobulin are inserted into a first immunoglobulin partnercomprising human variable framework sequences. Optionally, the firstimmunoglobulin partner is operatively linked to a second immunoglobulinpartner.

"First immunoglobulin partner" refers to a nucleic acid sequenceencoding a human framework or human immunoglobulin variable region inwhich the native (or naturally-occurring) CDR-encoding regions arereplaced by the CDR-encoding regions of a donor antibody. The humanvariable region can be an immunoglobulin heavy chain, a light chain (orboth chains), an analog or functional fragments thereof. Such CDRregions, located within the variable region of antibodies(immunoglobulins) can be determined by known methods in the art. Forexample Kabat et al. in "Sequences of Proteins of ImmunologicalInterest", 4th Ed., U.S. Department of Health and Human Services,National Institutes of Health (1987) disclose rules for locating CDRs.In addition, computer programs are known which are useful foridentifying CDR regions/structures.

"Second immunoglobulin partner" refers to another nucleotide sequenceencoding a protein or peptide to which the first immunoglobulin partneris fused in frame or by means of an optional conventional linkersequence (i.e., operatively linked). Preferably, it is an immunoglobulingene. The second immunoglobulin partner may include a nucleic acidsequence encoding the entire constant region for the same (i.e.,homologous, where the first and second altered antibodies are derivedfrom the same source) or an additional (i.e., heterologous) antibody ofinterest. It may be an immunoglobulin heavy chain or light chain (orboth chains as part of a single polypeptide). The second immunoglobulinpartner is not limited to a particular immunoglobulin class or isotype.In addition, the second immunoglobulin partner may comprise part of animmunoglobulin constant region, such as found in a Fab, or F(ab)₂ (i.e.,a discrete part of an appropriate human constant region or frameworkregion). Such second immunoglobulin partner may also comprise a sequenceencoding an integral membrane protein exposed on the outer surface of ahost cell, e.g., as part of a phage display library, or a sequenceencoding a protein for analytical or diagnostic detection, e.g.,horseradish peroxidase, β-galactosidase, etc.

The terms Fv, Fc, Fd, Fab, Fab' or F(ab')₂ are used with their standardmeanings. See, e.g., Harlow et al. in "Antibodies A Laboratory Manual",Cold Spring Harbor Laboratory, (1988).

As used herein, an "engineered antibody" describes a type of alteredantibody, i.e., a full-length synthetic antibody (e.g., a chimeric orhumanized antibody as opposed to an antibody fragment) in which aportion of the light and/or heavy chain variable domains of a selectedacceptor antibody are replaced by analogous parts from one or more donorantibodies which have specificity for the selected epitope. For example,such molecules may include antibodies characterized by a humanized heavychain associated with an unmodified light chain (or chimeric lightchain), or vice versa. Engineered antibodies may also be characterizedby alteration of the nucleic acid sequences encoding the acceptorantibody light and/or heavy variable domain framework regions in orderto retain donor antibody binding specificity. These antibodies cancomprise replacement of one or more CDRs (preferably all) from theacceptor antibody with CDRs from a donor antibody described herein.

A "chimeric antibody" refers to a type of engineered antibody whichcontains a naturally-occurring variable region (light chain and heavychains) derived from a donor antibody in association with light andheavy chain constant regions derived from an acceptor antibody.

A "humanized antibody" refers to a type of engineered antibody havingits CDRs derived from a non-human donor immunoglobulin, the remainingimmunoglobulin-derived parts of the molecule being derived from one ormore human immunoglobulins. In addition, framework support residues maybe altered to preserve binding affinity. See, e.g., Queen et al., Proc.Natl Acad Sci USA, 86, 10029-10032 (1989), Hodgson et al.,Bio/Technology, 9, 421 (1991).

The term "donor antibody" refers to a monoclonal or recombinant antibodywhich contributes the nucleic acid sequences of its variable regions,CDRs or other functional fragments or analogs thereof to a firstimmunoglobulin partner, so as to provide the altered immunoglobulincoding region and resulting expressed altered antibody with theantigenic specificity and neutralizing activity characteristic of thedonor antibody. One donor antibody suitable for use in this invention isa murine self-limiting neutralizing monoclonal antibody designated asBC2. Other suitable donor antibodies include the murine self-limitingneutralizing monoclonal antibodies designated as BC1, 9E4(2)F4,11G4(1)B9, HFXLC and HFXI.

The term "acceptor antibody" refers to monoclonal or recombinantantibodies heterologous to the donor antibody, which contributes all, ora portion, of the nucleic acid sequences encoding its heavy and/or lightchain framework regions and/or its heavy and/or light chain constantregions to the first immunoglobulin partner. Preferably, a humanantibody is the acceptor antibody.

"CDRs" are defined as the complementarity determining region amino acidsequences of an antibody which are the hypervariable regions ofimmunoglobulin heavy and light chains. See, e.g., Kabat et al.,Sequences of Proteins of Immunological Interest, 4th Ed., U.S.Department of Health and Human Services, National Institutes of Health(1987). There are three heavy chain and three light chain CDRs or CDRregions in the variable portion of an immunoglobulin. Thus, "CDRs" asused herein refers to all three heavy chain CDRs, or all three lightchain CDRs or both all heavy and all light chain CDRs, if appropriate.

CDRs provide the majority of contact residues for the binding of theantibody to the antigen or epitope. CDRs of interest in this inventionare derived from donor antibody variable heavy and light chainsequences, and include analogs of the naturally occurring CDRs, whichanalogs also share or retain the same antigen binding specificity and/orneutralizing ability as the donor antibody from which they were derived.

By "sharing the antigen binding specificity or neutralizing ability" ismeant, for example, that although mAb BC2 may be characterized by acertain level of self-limiting neutralizing activity, a CDR encoded by anucleic acid sequence of BC2 in an appropriate structural environmentmay have a lower, or higher activity. It is expected that CDRs of BC2 insuch environments will nevertheless recognize the same epitope(s) asBC2.

A "functional fragment" is a partial heavy or light chain variablesequence (e.g., minor deletions at the amino or carboxy terminus of theimmunoglobulin variable region) which retains the same antigen bindingspecificity and/or neutralizing ability as the antibody from which thefragment was derived.

An "analog" is an amino acid sequence modified by at least one aminoacid, wherein said modification can be chemical or a substitution or arearrangement of a few amino acids (i.e., no more than 10), whichmodification permits the amino acid sequence to retain the biologicalcharacteristics, e.g., antigen specificity and high affinity, of theunmodified sequence. Exemplary analogs include silent mutations whichcan be constructed, via substitutions, to create certain endonucleaserestriction sites within or surrounding CDR-encoding regions.

Analogs may also arise as allelic variations. An "allelic variation ormodification" is an alteration in the nucleic acid sequence encoding theamino acid or peptide sequences of the invention. Such variations ormodifications may be due to degeneracy in the genetic code or may bedeliberately engineered to provide desired characteristics. Thesevariations or modifications may or may not result in alterations in anyencoded amino acid sequence.

The term "effector agents" refers to non-protein carrier molecules towhich the altered antibodies, and/or natural or synthetic light or heavychains of the donor antibody or other fragments of the donor antibodymay be associated by conventional means. Such non-protein carriers caninclude conventional carriers used in the diagnostic field, e.g.,polystyrene or other plastic beads, polysaccharides, e.g., as used inthe BIAcore (Pharmacia) system, or other non-protein substances usefulin the medical field and safe for administration to humans and animals.Other effector agents may include a macrocycle, for chelating a heavymetal atom or radioisotopes. Such effector agents may also be useful toincrease the half-life of the altered antibodies, e.g., polyethyleneglycol.

For use in constructing the antibodies, altered antibodies and fragmentsof this invention, a non-human species such as bovine, ovine, monkey,chicken, rodent (e.g., murine and rat) may be employed to generate adesirable immunoglobulin upon presentment with a human coagulationfactor, preferably factor IX/IXa, X/Xa, XI/XIa, VIII/VIIIa, V/Va,VII/VIIa or thrombin or a peptide epitope therefrom. Conventionalhybridoma techniques are employed to provide a hybridoma cell linesecreting a non-human mAb to the respective coagulation factor. Suchhybridomas are then screened for binding using Factor IX/IXa, X/Xa,XI/XIa, VIII/VILIa, V/Va, VII/VIIa or thrombin coated to 96-well plates,as described in the Examples section, or alternatively with biotinylatedFactor IX/IXa, X/Xa, XI/XIa, VIII/VIIIa, V/Va, VII/VIIa or thrombinbound to a streptavidin-coated plate. Alternatively, fully human mAbscan be generated by techniques known to those skilled in the art andused in this invention.

One exemplary, self-limiting neutralizing mAb of this invention is mAbBC2, a murine antibody which can be used for the development of achimeric or humanized molecule. The BC2 mAb is characterized by aself-limiting inhibitory activity on clotting time. As measured by theaPTT assay, the effect of the BC2 mAb on clot time exhibits a maximalvalue of about 100 seconds. The BC2 mAb also binds Factor IXa, inhibitsFactor IX to IXa conversion and inhibits Factor IXa activity. Divalentmetal cofactors are required for activity, with the mAb exhibiting agreater preference for Ca²⁺ over Mn²⁺. The observed IC₅₀ in the aPTTassay is approximately 50 nM. The BC2 mAb exhibits a speciescross-reactivity with rat and is of isotype IgG2a.

Other desirable donor antibodies are the murine mAbs, BC1, 9E4(2)F4 and11G4(1)B9. These mAbs are characterized by a self-limiting inhibitoryactivity on clotting time. As measured by the aPTT assay, the effect ofthese mAbs on clot time exhibits a maximal value of about 90 to 100seconds for 9E4(2)F4 and about 80 seconds for 11G4(1)B9. The BC1 mAbalso binds Factor IXa, inhibits Factor IXa activity but does not inhibitFactor IX to IXa conversion. A metal cofactor is not required for itsactivity. The observed IC₅₀ for BC1 in the aPTT assay is approximately35 nM. The BC1 mAb is of isotype IgG1.

Yet another desirable donor antibody characterized by a self-limitinginhibitory activity on clotting time is the murine mAb HFXLC. Asmeasured by the aPTT assay, the effect of the HFXLC mAb on clot timeexhibits a maximal value of about 50 to 60 seconds. The HFXLC mAb bindsFactor X light chain, and inhibits Factor X/Xa activity. The observedIC₅₀ in the aPTT assay is approximately 20 nM.

Yet another desirable donor antibody characterized by a self-limitinginhibitory activity on clotting time is the murine mAb, HFXI. Asmeasured by the aPTT assay, the effect of the HFXI mAb on clot timeexhibits a maximal value of about 100 seconds. The HFXLC mAb bindsFactor XI and inhibits Factor XI/XIa activity. The observed IC₅₀ in theaPTT assay is approximately 30 nM.

While not intending to be bound to any particular theory regarding themechanism of action, these mAbs appear to regulate coagulation by anon-competitive or allosteric mechanism whereby only partial inhibitionis achieved.

This invention is not limited to the use of the BC1, BC2, 9E4(2)F4,11G4(1)B9, HFXLC, HFXI or their hypervariable (i.e., CDR) sequences. Anyother appropriate high-affinity antibodies characterized by aself-limiting neutralizing activity and corresponding CDRs may besubstituted therefor. Identification of the donor antibody in thefollowing description as BC1, BC2, 9E4(2)F4, 11G4(1)B9, HFXLC or HFXI ismade for illustration and simplicity of description only.

The present invention also includes the use of Fab fragments or F(ab')₂fragments derived from mAbs directed against the appropriate humancoagulation factor or cofactor. These fragments are useful as agentshaving self-limiting neutralizing activity against coagulation factors,preferably against Factor IX/IXa, X/Xa, Xi/XIa, VIII/VIIIa, V/Va,VII/VIIa or thrombin. A Fab fragment contains the entire light chain andamino terminal portion of the heavy chain. An F(ab')₂ fragment is thefragment formed by two Fab fragments bound by disulfide bonds. The mAbsBC1, BC2, 9E4(2)F4, 11G4(1)B9, HFXLC and HFXI and other similar highaffinity antibodies, provide sources of Fab fragments and F(ab')₂fragments which can be obtained by conventional means, e.g., cleavage ofthe mAb with the appropriate proteolytic enzymes, papain and/or pepsin,or by recombinant methods. These Fab and F(ab')₂ fragments are usefulthemselves as therapeutic, prophylactic or diagnostic agents, and asdonors of sequences including the variable regions and CDR sequencesuseful in the formation of recombinant or humanized antibodies asdescribed herein.

The Fab and F(ab')₂ fragments can be constructed via a combinatorialphage library (see, e.g., Winter et al., Ann. Rev. Immunol., 12:433-455(1994)) or via immunoglobulin chain shuffling (see, e.g., Marks et al.,Bio/Technology, 10:779-783 (1992), which are both hereby incorporated byreference in their entirety, wherein the Fd or v_(H) immunoglobulin froma selected antibody (e.g., BC2) is allowed to associate with arepertoire of light chain immunoglobulinsi v_(L) (or v_(K)), to formnovel Fabs. Conversely, the light chain immunoglobulin from a selectedantibody may be allowed to associate with a repertoire of heavy chainimmunoglobulins, v_(H) (or Fd), to form novel Fabs. Self-limitingneutralizing Factor IX Fabs can be obtained by allowing the Fd of mAbBC2 to associate with a repertoire of light chain immunoglobulins.Hence, one is able to recover neutralizing Fabs with unique sequences(nucleotide and amino acid) from the chain shuffling technique.

The mAb BC2 or other antibodies described above may contributesequences, such as variable heavy and/or light chain peptide sequences,framework sequences, CDR sequences, functional fragments, and analogsthereof, and the nucleic acid sequences encoding them, useful indesigning and obtaining various altered antibodies which arecharacterized by the antigen binding specificity of the donor antibody.

The nucleic acid sequences of this invention, or fragments thereof,encoding the variable light chain and heavy chain peptide sequences arealso useful for mutagenic introduction of specific changes within thenucleic acid sequences encoding the CDRs or framework regions, and forincorporation of the resulting modified or fusion nucleic acid sequenceinto a plasmid for expression. For example, silent substitutions in thenucleotide sequence of the framework and CDR-encoding regions can beused to create restriction enzyme sites which facilitate insertion ofmutagenized CDR and/or framework regions. These CDR-encoding regions canbe used in the construction of the humanized antibodies of theinvention.

The nucleic and amino acid sequences of the BC2 heavy chain variableregion are listed in SEQ ID NOs: 5 and 7. The CDR sequences from thisregion are listed in SEQ ID NOs: 8, 9 and 10.

The nucleic and amino acid sequences of the BC2 light chain variableregion are listed in SEQ ID NOs: 6 and 11. The CDR sequences from thisregion are listed in SEQ ID NOs: 12, 13 and 14.

Taking into account the degeneracy of the genetic code, various codingsequences may be constructed which encode the variable heavy and lightchain amino acid sequences and CDR sequences of the invention as well asfunctional fragments and analogs thereof which share the antigenspecificity of the donor antibody. The isolated nucleic acid sequencesof this invention, or fragments thereof, encoding the variable chainpeptide sequences or CDRs can be used to produce altered antibodies,e.g., chimeric or humanized antibodies or other engineered antibodies ofthis invention when operatively combined with a second immunoglobulinpartner.

It should be noted that in addition to isolated nucleic acid sequencesencoding portions of the altered antibody and antibodies describedherein, other such nucleic acid sequences are encompassed by the presentinvention, such as those complementary to the native CDR-encodingsequences or complementary to the modified human framework regionssurrounding the CDR-encoding regions. Useful DNA sequences include thosesequences which hybridize under stringent hybridization conditions tothe DNA sequences. See, T. Maniatis et al., Molecular Cloning (ALaboratory Manual), Cold Spring Harbor Laboratory (1982), pp. 387-389.An example of one such stringent hybridization condition ishybridization at 4×SSC at 65° C., followed by a washing in 0.1×SSC at65° C. for one hour. Alternatively, an exemplary stringent hybridizationcondition is 50% formamide, 4×SSC at 42° C. Preferably, thesehybridizing DNA sequences are at least about 18 nucleotides in length,i.e., about the size of a CDR.

Altered immunoglobulin molecules can encode altered antibodies whichinclude engineered antibodies such as chimeric antibodies and humanizedantibodies. A desired altered immunoglobulin coding region containsCDR-encoding regions that encode peptides having the antigen specificityof a Factor IX/IXa, X/Xa, XI/XIa, VIII/VIIIa, V/Va, VII/VIIa or thrombinantibody, preferably a high affinity antibody such as provided by thepresent invention, inserted into a first immunoglobulin partner such asa human framework or human immunoglobulin variable region.

Preferably, the first immunoglobulin partner is operatively linked to asecond immunoglobulin partner. The second immunoglobulin partner isdefined above, and may include a sequence encoding a second antibodyregion of interest, for example an Fc region. Second immunoglobulinpartners may also include sequences encoding another immunoglobulin towhich the light or heavy chain constant region is fused in frame or bymeans of a linker sequence. Engineered antibodies directed againstfunctional fragments or analogs of coagulation factors may be designedto elicit enhanced binding with the same antibody.

The second immunoglobulin partner may also be associated with effectoragents as defined above, including non-protein carrier molecules, towhich the second immunoglobulin partner may be operatively linked byconventional means.

Fusion or linkage between the second immunoglobulin partners, e.g.,antibody sequences, and the effector agent may be by any suitable means,e.g., by conventional covalent or ionic bonds, protein fusions, orhetero-bifunctional cross-linkers, e.g., carbodiimide, glutaraldehydeand the like. Such techniques are known in the art and are described inconventional chemistry and biochemistry texts.

Additionally, conventional linker sequences which simply provide for adesired amount of space between the second immunoglobulin partner andthe effector agent may also be constructed into the alteredimmunoglobulin coding region. The design of such linkers is well knownto those of skill in the art.

In addition, signal sequences for the molecules of the invention may bemodified by techniques known to those skilled in the art to enhanceexpression.

A preferred altered antibody contains a variable heavy and/or lightchain peptide or protein sequence having the antigen specificity of mAbBC2, e.g., the V_(H) and V_(L) chains. Still another desirable alteredantibody of this invention is characterized by the amino acid sequencecontaining at least one, and preferably all of the CDRs of the variableregion of the heavy and/or light chains of the murine antibody moleculeBC2 with the remaining sequences being derived from a human source, or afunctional fragment or analog thereof.

In a further embodiment, the altered antibody of the invention may haveattached to it an additional agent. For example, recombinant DNAtechnology may be used to produce an altered antibody of the inventionin which the Fc fragment or CH2 CH3 domain of a complete antibodymolecule has been replaced by an enzyme or other detectable molecule(i.e., a polypeptide effector or reporter molecule).

The second immunoglobulin partner may also be operatively linked to anon-immunoglobulin peptide, protein or fragment thereof heterologous tothe CDR-containing sequence having antigen specificity to a coagulationfactor, preferably to Factor IX/IXa, X/Xa, XI/XIa, VIII/VIIIa, V/Va,VII/VIIa or thrombin. The resulting protein may exhibit both antigenspecificity and characteristics of the non-immunoglobulin uponexpression. That fusion partner characteristic may be, e.g., afunctional characteristic such as another binding or receptor domain ora therapeutic characteristic if the fusion partner is itself atherapeutic protein or additional antigenic characteristics.

Another desirable protein of this invention may comprise a completeantibody molecule, having full length heavy and light chains or anydiscrete fragment thereof, such as the Fab or F(ab')₂ fragments, a heavychain dimer or any minimal recombinant fragments thereof such as anF_(v) or a single-chain antibody (SCA) or any other molecule with thesame specificity as the selected donor mAb, e.g., mAb BC1, BC2,9E4(2)F4, 11G4(1)B9, HFXLC or HFXI. Such protein may be used in the formof an altered antibody or may be used in its unfused form.

Whenever the second immunoglobulin partner is derived from an antibodydifferent from the donor antibody, e.g., any isotype or class ofimmunoglobulin framework or constant regions, an engineered antibodyresults. Engineered antibodies can comprise immunoglobulin (Ig) constantregions and variable framework regions from one source, e.g., theacceptor antibody, and one or more (preferably all) CDRs from the donorantibody, e.g., the anti-Factor IX/IXa, X/Xa, XI/XIa, VIII/VIIIa, V/Va,VII/VIIa or thrombin antibodies described herein. In addition,alterations, e.g., deletions, substitutions, or additions, of theacceptor mAb light and/or heavy variable domain framework region at thenucleic acid or amino acid levels, or the donor CDR regions may be madein order to retain donor antibody antigen binding specificity.

Such engineered antibodies are designed to employ one (or both) of thevariable heavy and/or light chains of the coagulation factor mAb(optionally modified as described) or one or more of the heavy or lightchain CDRs. The engineered antibodies of the invention exhibitself-limiting neutralizing activity.

Such engineered antibodies may include a humanized antibody containingthe framework regions of a selected human immunoglobulin or subtype or achimeric antibody containing the human heavy and light chain constantregions fused to the coagulation factor antibody functional fragments. Asuitable human (or other animal) acceptor antibody may be one selectedfrom a conventional database, e.g., the KABAT® database, Los Alamosdatabase, and Swiss Protein database, by homology to the nucleotide andamino acid sequences of the donor antibody. A human antibodycharacterized by a homology to the framework regions of the donorantibody (on an amino acid basis) may be suitable to provide a heavychain variable framework region for insertion of the donor CDRs. Asuitable acceptor antibody capable of donating light chain variableframework regions may be selected in a similar manner. It should benoted that the acceptor antibody heavy and light chains are not requiredto originate from the same acceptor antibody.

Preferably, the heterologous framework and constant regions are selectedfrom human immunoglobulin classes and isotypes, such as IgG (subtypes 1through 4), IgM, IgA, and IgE. However, the acceptor antibody need notcomprise only human immunoglobulin protein sequences. For instance, agene may be constructed in which a DNA sequence encoding part of a humanimmunoglobulin chain is fused to a DNA sequence encoding anon-immunoglobulin amino acid sequence such as a polypeptide effector orreporter molecule.

A particularly preferred humanized antibody contains CDRs of BC2inserted onto the framework regions of a selected human antibodysequence. For neutralizing humanized antibodies, one, two or preferablythree CDRs from the Factor IX antibody heavy chain and/or light chainvariable regions are inserted into the framework regions of the selectedhuman antibody sequence, replacing the native CDRs of the latterantibody.

Preferably, in a humanized antibody, the variable domains in both humanheavy and light chains have been engineered by one or more CDRreplacements. It is possible to use all six CDRs, or variouscombinations of less than the six CDRs. Preferably all six CDRs arereplaced. It is possible to replace the CDRs only in the human heavychain, using as light chain the unmodified light chain from the humanacceptor antibody. Still alternatively, a compatible light chain may beselected from another human antibody by recourse to the conventionalantibody databases. The remainder of the engineered antibody may bederived from any suitable acceptor human immunoglobulin.

The engineered humanized antibody thus preferably has the structure of anatural human antibody or a fragment thereof, and possesses thecombination of properties required for effective therapeutic use, e.g.,treatment of thrombotic and embolic diseases in man.

Most preferably, the humanized antibodies have a heavy chain amino acidsequence as set forth in SEQ ID NO: 31, 52, or 89. Also most preferredare humanized antibodies having a light chain amino acid sequence as setforth in SEQ ID NO: 44, 57, 62, 74, 78 or 99. Particularly preferred isthe humanized antibody SB 249413 where the heavy chain has the aminoacid sequence as set forth in SEQ ID NO: 31 and the light chain has theamino acid sequence as set forth in SEQ ID NO: 44. Also particularlypreferred is the humanized antibody SB 249415 where the heavy chain hasthe amino acid sequence as set forth in SEQ ID NO: 52 and the lightchain has the amino acid sequence as set forth in SEQ ID NO: 57. Alsoparticularly preferred is the humanized antibody SB 249416 where theheavy chain has the amino acid sequence as set forth in SEQ ID NO: 52and the light chain has the amino acid sequence as set forth in SEQ IDNO: 62. Also particularly preferred is the humanized antibody SB 249417where the heavy chain has the amino acid sequence as set forth in SEQ IDNO: 52 and the light chain has the amino acid sequence as set forth inSEQ ID NO: 74. Also particularly preferred is the humanized antibody SB257731 where the heavy chain has the amino acid sequence as set forth inSEQ ID NO: 52 and the light chain has the amino acid sequence as setforth in SEQ ID NO: 78. Also particularly preferred is the humanizedantibody SB 257732 where the heavy chain has the amino acid sequence asset forth in SEQ ID NO: 89 and the light chain has the amino acidsequence as set forth in SEQ ID NO: 99.

It will be understood by those skilled in the art that an engineeredantibody may be further modified by changes in variable domain aminoacids without necessarily affecting the specificity and high affinity ofthe donor antibody (i.e., an analog). It is anticipated that heavy andlight chain amino acids may be substituted by other amino acids eitherin the variable domain frameworks or CDRs or both. These substitutionscould be supplied by the donor antibody or consensus sequences from aparticular subgroup.

In addition, the constant region may be altered to enhance or decreaseselective properties of the molecules of this invention. For example,dimerization, binding to Fc receptors, or the ability to bind andactivate complement (see, e.g., Angal et al., Mol. Immunol, 30, 105-108(1993), Xu et al., J. Biol. Chem, 269, 3469-3474 (1994), Winter et al.,EP 307434-B).

An altered antibody which is a chimeric antibody differs from thehumanized antibodies described above by providing the entire non-humandonor antibody heavy chain and light chain variable regions, includingframework regions, in association with human immunoglobulin constantregions for both chains. It is anticipated that chimeric antibodieswhich retain additional non-human sequence relative to humanizedantibodies of this invention may elicit a significant immune response inhumans.

Such antibodies are useful in the prevention and treatment of thromboticand embolic disorders, as discussed below.

Preferably, the variable light and/or heavy chain sequences and the CDRsof mAb BC2 or other suitable donor mAbs, e.g., BC1, 9E4(2)F4, 11G4(1)B9,HFXLC, HFXI, and their encoding nucleic acid sequences, are utilized inthe construction of altered antibodies, preferably humanized antibodies,of this invention, by the following process. The same or similartechniques may also be employed to generate other embodiments of thisinvention.

A hybridoma producing a selected donor mAb, e.g., the murine antibodyBC2, is conventionally cloned and the DNA of its heavy and light chainvariable regions obtained by techniques known to one of skill in theart, e.g., the techniques described in Sambrook et al., "MolecularCloning: A Laboratory Manual", 2nd edition, Cold Spring HarborLaboratory (1989). The variable heavy and light regions of BC2containing at least the CDR-encoding regions and those portions of theacceptor mAb light and/or heavy variable domain framework regionsrequired in order to retain donor mAb binding specificity, as well asthe remaining immunoglobulin-derived parts of the antibody chain derivedfrom a human immunoglobulin, are obtained using polynucleotide primersand reverse transcriptase. The CDR-encoding regions are identified usinga known database and by comparison to other antibodies.

A mouse/human chimeric antibody may then be prepared and assayed forbinding ability. Such a chimeric antibody contains the entire non-humandonor antibody V_(H) and V_(L) regions, in association with human Igconstant regions for both chains.

Homologous framework regions of a heavy chain variable region from ahuman antibody are identified using computerized databases, e.g.,KABAT®, and a human antibody having homology to BC2 is selected as theacceptor antibody. The sequences of synthetic heavy chain variableregions containing the BC2 CDR-encoding regions within the humanantibody frameworks are designed with optional nucleotide replacementsin the framework regions to incorporate restriction sites. This designedsequence is then synthesized using long synthetic oligomers.Alternatively, the designed sequence can be synthesized by overlappingoligonucleotides, amplified by polymerase chain reaction (PCR), andcorrected for errors. A suitable light chain variable framework regioncan be designed in a similar manner.

A humanized antibody may be derived from the chimeric antibody, orpreferably, made synthetically by inserting the donor mAb CDR-encodingregions from the heavy and light chains appropriately within theselected heavy and light chain framework. Alternatively, a humanizedantibody of the invention may be prepared using standard mutagenesistechniques. Thus, the resulting humanized antibody contains humanframework regions and donor mAb CDR-encoding regions. There may besubsequent manipulation of framework residues. The resulting humanizedantibody can be expressed in recombinant host cells, e.g., COS, CHO ormyeloma cells. Other humanized antibodies may be prepared using thistechnique on other suitable Factor IX-specific or other coagulationfactor-specific, self-limiting, neutralizing, high affinity, non-humanantibodies.

A conventional expression vector or recombinant plasmid is produced byplacing these coding sequences for the altered antibody in operativeassociation with conventional regulatory control sequences capable ofcontrolling the replication and expression in, and/or secretion from, ahost cell. Regulatory sequences include promoter sequences, e.g., CMVpromoter, and signal sequences, which can be derived from other knownantibodies. Similarly, a second expression vector can be produced havinga DNA sequence which encodes a complementary antibody light or heavychain. Preferably, this second expression vector is identical to thefirst except with respect to the coding sequences and selectablemarkers, in order to ensure, as much as possible, that each polypeptidechain is functionally expressed. Alternatively, the heavy and lightchain coding sequences for the altered antibody may reside on a singlevector.

A selected host cell is co-transfected by conventional techniques withboth the first and second vectors (or simply transfected by a singlevector) to create the transfected host cell of the invention comprisingboth the recombinant or synthetic light and heavy chains. Thetransfected cell is then cultured by conventional techniques to producethe engineered antibody of the invention. The humanized antibody whichincludes the association of both the recombinant heavy chain and/orlight chain is screened from culture by an appropriate assay such asELISA or RIA. Similar conventional techniques may be employed toconstruct other altered antibodies and molecules of this invention.

Suitable vectors for the cloning and subcloning steps employed in themethods and construction of the compositions of this invention may beselected by one of skill in the art. For example, the pUC series ofcloning vectors, such as pUC19, which is commercially available fromsupply houses, such as Amersham or Pharmacia, may be used. Additionally,any vector which is capable of replicating readily, has an abundance ofcloning sites and selectable genes (e.g., antibiotic resistance) and iseasily manipulated may be used for cloning. Thus, the selection of thecloning vector is not a limiting factor in this invention.

Similarly, the vectors employed for expression of the engineeredantibodies according to this invention may be selected by one of skillin the art from any conventional vector. The vectors also containselected regulatory sequences (such as CMV promoters) which direct thereplication and expression of heterologous DNA sequences in selectedhost cells. These vectors contain the above-described DNA sequenceswhich code for the engineered antibody or altered immunoglobulin codingregion. In addition, the vectors may incorporate the selectedimmunoglobulin sequences modified by the insertion of desirablerestriction sites for ready manipulation.

The expression vectors may also be characterized by genes suitable foramplifying expression of the heterologous DNA sequences, e.g., themammalian dihydrofolate reductase gene (DHFR). Other preferable vectorsequences include a poly A signal sequence, such as from bovine growthhormone (BGH) and the betaglobin promoter sequence (betaglopro). Theexpression vectors useful herein may be synthesized by techniques wellknown to those skilled in this art.

The components of such vectors, e.g., replicons, selection genes,enhancers, promoters, signal sequences and the like, may be obtainedfrom commercial or natural sources or synthesized by known proceduresfor use in directing the expression and/or secretion of the product ofthe recombinant DNA in a selected host. Other appropriate expressionvectors of which numerous types are known in the art for mammalian,bacterial, insect, yeast and fungal expression may also be selected forthis purpose.

The present invention also encompasses a cell line transfected with arecombinant plasmid containing the coding sequences of the engineeredantibodies or altered immunoglobulin molecules thereof. Host cellsuseful for the cloning and other manipulations of these cloning vectorsare also conventional. However, most desirably, cells from variousstrains of E. coli are used for replication of the cloning vectors andother steps in the construction of altered antibodies of this invention.

Suitable host cells or cell lines for the expression of the engineeredantibody or altered antibody of the invention are preferably mammaliancells such as CHO, COS, a fibroblast cell (e.g., 3T3) and myeloid cells,and more preferably a CHO or a myeloid cell. Human cells may be used,thus enabling the molecule to be modified with human glycosylationpatterns. Alternatively, other eukaryotic cell lines may be employed.The selection of suitable mammalian host cells and methods fortransformation, culture, amplification, screening and product productionand purification are known in the art. See, e.g., Sambrook et al.,supra.

Bacterial cells may prove useful as host cells suitable for theexpression of the recombinant Fabs of the present invention (see, e.g.,Pluckthun, A., Immunol. Rev., 130, 151-188 (1992)). However, due to thetendency of proteins expressed in bacterial cells to be in an unfoldedor improperly folded form or in a non-glycosylated form, any recombinantFab produced in a bacterial cell would have to be screened for retentionof antigen binding ability. If the molecule expressed by the bacterialcell was produced in a properly folded form, that bacterial cell wouldbe a desirable host. For example, various strains of E. coli used forexpression are well-known as host cells in the field of biotechnology.Various strains of B. subtilis, Streptomyces, other bacilli and the likemay also be employed.

Where desired, strains of yeast cells known to those skilled in the artare also available as host cells, as well as insect cells, e.g.Drosophila and Lepidoptera and viral expression systems. See, e.g.Miller et al., Genetic Engineering, 8, 277-298, Plenum Press (1986) andreferences cited therein.

The general methods by which the vectors of the invention may beconstructed, the transfection methods required to produce the host cellsof the invention, and culture methods necessary to produce the alteredantibody of the invention from such host cell are all conventionaltechniques. Likewise, once produced, the altered antibodies of theinvention may be purified from the cell culture contents according tostandard procedures of the art, including ammonium sulfateprecipitation, affinity columns, column chromatography, gelelectrophoresis and the like. Such techniques are within the skill ofthe art and do not limit this invention.

Yet another method of expression of the humanized antibodies may utilizeexpression in a transgenic animal, such as described in U.S. Pat. No.4,873,316. This relates to an expression system using the animal'scasein promoter which when transgenically incorporated into a mammalpermits the female to produce the desired recombinant protein in itsmilk.

Once expressed by the desired method, the engineered antibody is thenexamined for in vitro activity by use of an appropriate assay.Presently, conventional ELISA assay formats are employed to assessqualitative and quantitative binding of the engineered antibody toFactor IX or to other appropriate coagulation factors. Additionally,other in vitro assays may also be used to verify neutralizing efficacyprior to subsequent human clinical studies performed to evaluate thepersistence of the engineered antibody in the body despite the usualclearance mechanisms.

Following the procedures described for humanized antibodies preparedfrom BC2, one of skill in the art may also construct humanizedantibodies from other donor antibodies, variable region sequences andCDR peptides described herein. Engineered antibodies can be producedwith variable region frameworks potentially recognized as "self" byrecipients of the engineered antibody. Minor modifications to thevariable region frameworks can be implemented to effect large increasesin antigen binding without appreciable increased immunogenicity for therecipient. Such engineered antibodies may effectively treat a human forcoagulation factor-mediated conditions. Such antibodies may also beuseful in the diagnosis of such conditions.

This invention also relates to a method for inhibiting thrombosis in ananimal, particularly a human, which comprises administering an effectivedose of an anti-coagulation factor monoclonal antibody havingself-limiting neutralizing activity. Preferably, the coagulation factoris from the intrinsic or common coagulation pathway. Most preferably,the anti-coagulation factor monoclonal antibody is an anti-Factor IX,anti-Factor Ixa, anti-Factor X, anti-Factor Xa, anti-Factor XI,anti-Factor XIa, anti-Factor VIII, anti-Factor VIIIa, anti-Factor V,anti-Factor Va, anti-Factor VII, anti-Factor VIIa or anti-thrombin. ThemAb can include one or more of the engineered antibodies or alteredantibodies described herein or fragments thereof.

Alternatively, acetylsalicylic acid can be administered in combinationwith the anti-coagulation factor monoclonal antibody. In some cases,combination therapy lowers the therapeutically effective dose ofanti-coagulation factor monoclonal antibody.

The therapeutic response induced by the use of the molecules of thisinvention is produced by the binding to the respective coagulationfactor and the subsequent self-limiting inhibition of the coagulationcascade. Thus, the molecules of the present invention, when inpreparations and formulations appropriate for therapeutic use, arehighly desirable for persons susceptible to or experiencing abnormalclotting activity associated with, but not limited to, myocardialinfarction, unstable angina, atrial fibrillation, stroke, renal damage,pulmonary embolism, deep vein thrombosis and artificial organ andprosthetic implants.

The altered antibodies, antibodies and fragments thereof of thisinvention may also be used in conjunction with other antibodies,particularly human mAbs reactive with other markers (epitopes)responsible for the condition against which the engineered antibody ofthe invention is directed.

The therapeutic agents of this invention are believed to be desirablefor treatment of abnormal clotting conditions from about 1 day to about3 weeks, or as needed. This represents a considerable advance over thecurrently used anticoagulants heparin and warfarin. The dose andduration of treatment relates to the relative duration of the moleculesof the present invention in the human circulation, and can be adjustedby one of skill in the art depending upon the condition being treatedand the general health of the patient.

The mode of administration of the therapeutic agent of the invention maybe any suitable route which delivers the agent to the host. The alteredantibodies, antibodies, engineered antibodies, and fragments thereof,and pharmaceutical compositions of the invention are particularly usefulfor parenteral administration, i.e., subcutaneously, intramuscularly,intravenously or intranasally.

Therapeutic agents of the invention may be prepared as pharmaceuticalcompositions containing an effective amount of the engineered (e.g.,humanized) antibody of the invention as an active ingredient in apharmaceutically acceptable carrier. Alternatively, the pharmaceuticalcompositions of the invention could also contain acetysalicylic acid. Inthe prophylactic agent of the invention, an aqueous suspension orsolution containing the engineered antibody, preferably buffered atphysiological pH, in a form ready for injection is preferred. Thecompositions for parenteral administration will commonly comprise asolution of the engineered antibody of the invention or a cocktailthereof dissolved in an pharmaceutically acceptable carrier, preferablyan aqueous carrier. A variety of aqueous carriers may be employed, e.g.,0.4% saline, 0.3% glycine and the like. These solutions are sterile andgenerally free of particulate matter. These solutions may be sterilizedby conventional, well known sterilization techniques (e.g., filtration).The compositions may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, etc. The concentration of theantibody of the invention in such pharmaceutical formulation can varywidely, i.e., from less than about 0.5%, usually at or at least about 1%to as much as 15 or 20% by weight and will be selected primarily basedon fluid volumes, viscosities, etc., according to the particular mode ofadministration selected.

Thus, a pharmaceutical composition of the invention for intramuscularinjection could be prepared to contain 1 mL sterile buffered water, andbetween about 1 ng to about 100 mg, e.g. about 50 ng to about 30 mg ormore preferably, about 5 mg to about 25 mg, of an engineered antibody ofthe invention. Similarly, a pharmaceutical composition of the inventionfor intravenous infusion could be made up to contain about 250 ml ofsterile Ringer's solution, and about 1 mg to about 30 mg and preferably5 mg to about 25 mg of an engineered antibody of the invention. Actualmethods for preparing parenterally administrable compositions are wellknown or will be apparent to those skilled in the art and are describedin more detail in, for example, "Remington's Pharmaceutical Science",15th ed., Mack Publishing Company, Easton, Pa.

It is preferred that the therapeutic agent of the invention, when in apharmaceutical preparation, be present in unit dose forms. Theappropriate therapeutically effective dose can be determined readily bythose of skill in the art. To effectively treat a thrombotic or embolicdisorder in a human or other animal, one dose of approximately 0.1 mg toapproximately 20 mg per kg body weight of a protein or an antibody ofthis invention should be administered parenterally, preferably i.v. ori.m. Such dose may, if necessary, be repeated at appropriate timeintervals selected as appropriate by a physician during the thromboticresponse.

The antibodies, altered antibodies or fragments thereof described hereincan be lyophilized for storage and reconstituted in a suitable carrierprior to use. This technique has been shown to be effective withconventional immunoglobulins and art-known lyophilization andreconstitution techniques can be employed.

The present invention will now be described with reference to thefollowing specific, non-limiting examples.

EXAMPLE 1 Preparation and Screening of Anti-Factor IX MonoclonalAntibodies

Female Balb/C mice were injected with human factor IX purified asdescribed in Jenny, R. et al., Prep.Biochem. 16, 227-245 (1986).Typically, each mouse received an initial injection of 100 ug proteindissolved in 0.15 mL phosphate-buffered saline (PBS) and mixed with 0.15mL complete Freund's adjuvant. Booster immunizations of 50 ug protein in0.15 mL PBS with 0.15 mL incomplete Freund's adjuvant were givenapproximately biweekly over a 2-3 month period. After the final boost,the mouse received 50 ug of Factor IX in PBS three days beforespleen/myeloma cell fusions. Spleen cells were isolated from animmunized mouse and fused with NS-1 myeloma cells (Kohler, G. et al.,Eur. J. Immunol. 6, 292-295 (1976)) using polyethylene glycol asdescribed by Oi, V. T. et al. in "Selected Methods in CellularImmunology," Mishell, B. B. and Shigii, S. M., eds., Freeman Press, SanFrancisco. Following the fusion, the cells were resuspended in RPMI 1640media containing 10% fetal calf sera and aliquots were placed in eachwell of four 24-well plates containing 0.5 mL of peritoneal lavagecell-conditioned media. On the following day, each well received 1.0 mLof 2×10⁻⁴ M hypoxanthine, 8×10⁻⁷ M aminopterin and 3.2×10⁻⁵ M thymidinein RPMI 1640 media containing 10% fetal calf sera. The cells were fedevery 3-4 days by removing half of the media and replacing it with freshmedia containing 1×10⁻⁴ M hypoxanthine and 1.6×10⁻⁵ M thymidine.

Approximately two weeks later, 1.0 mL of hybridoma medium was removedfrom each well and tested for anti-Factor IX antibodies using an ELISAassay as described by Jenny, R. J. et al. in Meth. Enzymol. 222, 400-416(1993). Briefly, factor IX was immmobilized onto plastic wells of96-well microtiter plates. Hybridoma supernatants or dilutions ofpurified antibody were then incubated in the wells. The wells werewashed and the presence of antibody-antigen complexes detected with agoat anti-murine immunoglobulin second antibody conjugated tohorseradish peroxidase and the chromogenic substrate o-dianisidine.

Wells containing anti-Factor IX antibodies were subcloned by limitingdilution and grown in 96-well plates. Supernatant from the clonedhybridoma cell cultures were screened for antibody to Factor IX by theELISA assay described above and cells from positive hybridomas wereexpanded, frozen, stored in liquid nitrogen and then grown as ascitictumors in mice.

EXAMPLE 2 Self-Limiting Effect of Anti-Coagulation Factor Antibodies inCoagulation

The effect of increasing concentrations of anti-coagulation factorantibodies on activated partial thromboplastin time (aPTT) of humanplasma was determined in a fibrometer (Becton-Dickinson MicrobiologySystems, Cockeysville, Md.) using Baxter reference procedure LIB0293-J,3/93 revision (Baxter Scientific, Edison, N.J.).

Prior to the start of the experiment, 2 to 3 mL of 0.02 M CaCl₂ in a 5mL tube were placed into the heating chamber of the fibrometer. Humanplasma samples were either freshly drawn and kept on ice orreconstituted per the manufacturer's recommendation from HemostasisReference Plasma (American Diagnostics, Greenwich, Conn.).

Unfractionated heparin from porcine intestinal mucosa (Sigma Chemical,St. Louis, Mo.), low molecular weight heparin from porcine intestinalmucosa (Lovenox®, enoxaparin sodium, Rhone-Poulenc RorerPharmaceuticals, Collegeville, Pa.) or mAb anticoagulants were preparedas approximately 50 uM stock solutions and serially diluted directlyinto the test plasma. A blank containing plasma without anticoagulantwas included as a reference.

Two fibroTube® fibrometer cups were filled with 100 ul test plasma or100 ul test plasma with anticoagulant and 125 ul of actin activatedcephaloplastin reagent (Actin reagent, from rabbit brain cephalin inellagic acid, available from Baxter Scientific), respectively and placedin the fibrometer wells at 37° C.

After one minute, 100 ul of actin reagent was transferred to aplasma-containing cup and the contents mixed several times with apipette. After a 3 minute incubation, 100 ul of CaCl₂, prewarmed at 37°C., was added to the plasma-actin reagent mixture using a AutomaticPipette/Timer-trigger (Becton-Dickinson). The clotting times were notedand the results in FIG. 1 are presented as clotting times as a functionof final concentrations of anticoagulant in the total assay volume of300 ul. The nominal concentration of Factor IX in the assay is 30-40 nM.

The results shown in FIG. 1 demonstrate the effect of increasingconcentrations of the murine anti-Factor IX mAbs BC1 and BC2 on aPTTclotting times. Both mAbs inhibit clotting by prolonging the aPTT andboth mAbs reach a final saturating effect on the aPTT. The IC₅₀ valuesare similar at ˜35 nM and ˜50 nM for BC1 and BC2, respectively, but thedifference in the maximum response to the two antibodies is marked.Saturating concentrations of BC1 increases the aPTT by about 50% to ˜40sec. BC2, on the other hand, increases the aPTT by 3.5-fold to about 90sec. The therapeutic target zone used in anticoagulant therapy withheparin is highlighted. The results indicate that the two mAbs bracketthe heparin therapeutic aPTT range.

The properties of mAbs BC1 and BC2 are summarized in Table I. Each ofthe BC mAbs recognizes both the zymogen, Factor IX, as well as theactive protease, Factor IXa, but only BC2 is capable of blocking bothzymogen activation as well as protease activity. BC1 and BC2 were foundto cross-react with Cynomologous monkey Factor IX. Additionally, BC2also cross-reacted with rat Factor IX.

                  TABLE I                                                         ______________________________________                                        Summary of in vitro Properties of Anti-Factor                                  IX mAbs                                                                                       BC1        BC2                                               ______________________________________                                        Binds Factor IX  yes        yes                                                 Binds Factor IXa yes yes                                                      Inhibits IX to IXa no yes                                                     conversion                                                                    Inhibits IXa activity yes yes                                                 in Xase complex                                                               Cofactor requirement none divalent                                              metals                                                                        Ca.sup.2+  > Mn.sup.2+                                                      aPTTmax × 100% 150 350                                                  aPTTnormal                                                                    IC.sub.50, nM ˜35 ˜50                                             Species cross- monkey rat, monkey                                             reactivity                                                                    Isotype IgG1 IgG2a                                                          ______________________________________                                    

The results shown in FIG. 2 demonstrate the effect of increasingconcentrations of the anti-Factor IX mAbs 9E4(2)F4 and 11G4(1)B9 on aPTTclotting times. The plasma for the assay was diluted to one-half thenormal concentration, giving an initial aPTT of 45 seconds. Both mAbsinhibit clotting by prolonging the aPTT and both mAbs reach a finalsaturating effect on the aPTT. Saturating concentrations of 9E4(2)F4 and11G4(1)B9 increases the aPTT to ˜90 to 100 seconds for 9E4(2)F4 and to˜80 seconds for 11G4(1)B9. The results indicate that the two mAbs are atthe upper end of the heparin therapeutic aPTT range.

The results shown in FIG. 3 demonstrate the effect of increasingconcentrations of the anti-Factor X mAbs HFXLC (vs. light chainepitope), HFXHC (vs. heavy chain epitope) and the anti-Factor XI mabHFXI on aPTT clotting times. These mAbs were obtained from EnzymeResearch Laboratories (South Bend, Ind.). The mabs HFXLC and HFXIinhibit clotting by prolonging the aPTT and both mAbs reach a finalsaturating effect on the aPTT. The IC₅₀ value for HFXLC is ˜40 nM;saturating concentrations increase the aPTT to ˜60 seconds. The IC₅₀value for HFXI is ˜20 nM; saturating concentrations increase the aPTT to˜100 seconds. The results indicate that HFXLC is within the heparintherapeutic aPTT range while HFXI falls at the upper end of the heparintherapeutic range. The mAb HFXHC had no effect on aPTT clotting times.

Self-limiting prolongation of the aPTT was also observed with antibodiesto Factor VIII, the cofactor to Factor IXa. For example, the anti-humanFactor VIII antibody, SAF8C-IG, purchased from Affinity Biologicals,Inc., increased the aPTT to a maximum of about 65 sec. Half-maximalprolongation of the aPTT was achieved with about 100 nM antibody.

EXAMPLE 3 Efficacy of Murine Factor IX mAbs in Rat Thrombus Model

In order to evaluate the efficacy of anti-Factor IX antibodies inprevention of arterial thrombosis, the rat carotid artery thrombosismodel as reported by Schumacher et al. in J. Cardio. Pharm. 22, 526-533(1993) was adapted. This model consists of segmental injury to thecarotid endothelium by oxygen radicals generated by FeCl₃ solutionapplied on the surface of the carotid artery.

In brief, rats were anesthetized with pentobarbitone sodium, the jugularvein cannulated for intravenous injections and the left femoral arterycannulated for blood pressure and heart rate monitoring. The carotidartery was isolated by aseptic technique via a surgical incision in theneck and equipped with a magnetic flow probe for blood flow measurement.After a period of stabilization, baseline parameters were establishedfor the following variables: carotid blood flow, arterial pressure,heart rate, activated partial thromboplastin time (aPTT) and prothrombintime (PT). Thereafter, a premeasured Whatman filter paper soaked in 50%FeCl₃ solution was placed on the carotid artery for 15 minutes forcomplete injury of the underlying endothelial cells. After removal ofthe FeCl₃ soaked paper, the experiment was followed to completion over60 minutes. At the end of the experiment, the carotid thrombus wasextracted from the carotid artery and weighed.

All agents were administered 15 minutes prior to the onset of carotidinjury. The following treatments were examined and compared to theFactor IX mAb BC2.

1. Heparin: 15, 30, 60 or 120 U/kg bolus, followed by infusion of 0.5,1, 2 or 4 U/kg/min, respectively over 60 minutes

2. Acetylsalicylic acid (ASA, aspirin): 5 mg/kg bolus

3. Anti-Factor IX mAb BC2: 1, 3 or 6 mg/kg bolus, followed by infusion0.3, 1, or 2 ug/kg/min, respectively over 60 minutes

4. Heparin: 30 OU/kg bolus+1 U/kg/min+ASA at 5 mg/kg

5. Anti-Factor IX mAb BC2: 1 mg/kg+0.3 ug/kg/min+ASA at 5 mg/kg

FIGS. 4 and 5 demonstrate the comparative pharmacology of theanti-coagulant/thrombotic regimens by showing the effect of heparin, ASAand Factor IX mAb BC2 on aPTT (FIG. 4) and PT (FIG. 5).

The key index for bleeding diathesis, aPTT, was used as the primarycriterion for evaluation of efficacy versus bleeding liabilities of theanti-coagulant/thrombotic agents used in the study. The results in FIG.4 demonstrate the dose-dependent prolongation of aPTT by heparin withmaximal prolongation of the clotting time, beyond the test limit, at thetwo higher doses. ASA alone did not significantly increase aPTT but incombination with heparin, a marked synergistic effect was observed. TheFactor IX mAbs had a modest effect on aPTT and even at the highest dose,the increase in clotting time did not exceed the 3-fold limit ofstandard anti-coagulant practiced clinically. Most notably, the low doseof Factor IX mAb BC2 in combination with ASA did not change the aPTT.

In FIG. 5, the data indicate that PT was also significantly prolonged byheparin, at the two higher doses, and by the ASA+heparin combination,but not by any of the Factor IX mAb doses alone or in combination withASA.

The effect of heparin, ASA and Factor IX mAb on carotid artery occlusionis shown in FIG. 6. The results indicate that the carotid arteries ofall of the vehicle-treated animals occlude in response to the injury.Heparin dose dependently inhibited the occlusion of the carotid artery.At the highest dose, heparin completely prevented the occlusion of thecarotid artery; at this dose however, no coagulation could be initiated.ASA alone had only a minor effect on carotid occlusion. ASA incombination with heparin also failed to completely prevent carotidocclusion. Factor IX mAb completely blocked carotid occlusion at the twohigher doses, which have not prolonged coagulation beyond the clinicallydesired target. The lower dose of Factor IX mAb, that largely failed tosecure patency alone, demonstrated complete inhibition of carotidocclusion when administered in combination with ASA.

The effect of heparin, ASA and Factor IX mAb on thrombus weight is shownin FIG. 7. Heparin dose-dependently reduced thrombus mass in the carotidartery. However, some residual thrombus was still found in the carotidartery in spite of complete blockade of coagulation. ASA alone or incombination with heparin (30 U/kg regimen) had only a partial effect onthrombus weight. Factor IX mAb dose-dependently reduced thrombus massand the high dose virtually prevented completely thrombus formation.Moreover, the combination of the low dose anti-Factor IX mAb and ASA, aregimen that completely prevented carotid occlusion without adverselyaffecting the coagulation indices, completely prevented thrombusformation.

The studies conducted in the rat carotid thrombosis model clearlydemonstrate the efficacy of Factor IX mAb in prevention of thrombosis ina highly thrombogenic arterial injury model. Most notably, the efficacyof the Factor IX mAb was demonstrated within the desired therapeuticanticoagulant target defined by the aPTT. Furthermore, heparin, thecurrent standard anticoagulant, reached efficacy comparable to Factor IXmAb only at doses that severely compromised coagulation to the extent ofproducing non-coagulable blood. Interestingly, the observed potentiationand synergy acquired by ASA joint treatment with heparin was alsodemonstrated when ASA was given with anti-Factor IX mAb. However, unlikethe combination of heparin and ASA which resulted in potentiation ofboth the anti-thrombotic and anti-coagulant effects, the combination ofFactor IX mAb and ASA resulted in potentiation of the anti-thromboticefficacy with no consistent effect on ex vivo blood coagulationparameters. Taken together, the data show a superior antithromboticcapacity of Factor IX mAb compared to heparin, ASA or a combination ofheparin and ASA.

EXAMPLE 4 Scanning Electron Microscopy of Rat Thrombosis Model

Segments of rat carotid artery were collected from sham, ferric chlorideonly and ferric chloride+6 mg/kg Factor IX antibody, 3/group, 15 minutesafter application of ferric chloride. The arteries were fixed byperfusion with formaldehyde and ligated above and below the lesionedarea. Fixed arteries were dehydrated, incubated in hexamethyldisilazaneand dried in a desiccator. Dried arteries were opened lengthwise, placedon Scanning Electron Microscopy (SEM) stubs and sputter coated withgold.

SEM of sham arteries revealed an essentially normal endothelium withrare scattered platelets. There were a few breaks in the endothelium,probably as a result of mechanical damage during surgery and theunderlying basement membrane was covered by a carpet of platelets. Noevidence of thrombus formation was observed in the sham rats.

SEM of the arteries treated with ferric chloride revealed large muralthrombi which occupied a large portion of the lumen of the vessel. Thethrombi were composed of aggregated platelets, red blood cells andamorphous and fibrillar proteinaceous material. The proteinaceousmaterial is consistent with fibrin. The endothelium of the arteries wasmostly obscured by the large thrombi. Where visible, the endotheliumoverlying the region treated with ferric chloride was covered bynumerous adherent platelets and amorphous proteinaceous material.

SEM of the arteries treated with ferric chloride from rats also treatedwith Factor IX antibody, revealed the lumen of the vessels to be largelyfree of thrombus. The endothelium overlying the region treated withferric chloride showed extensive damage and some areas were covered byadherent platelets and platelet aggregates but there was little or noproteinaceous material.

EXAMPLE 5 Anti-Factor IX mAb BC2 Heavy and Light Chain cDNA SequenceAnalysis

Total RNA was purified by using TriReagent (Molecular Research Center,Inc., Cincinnati, Ohio) according to the manufacturer's protocol. RNAwas precipitated with isopropanol and dissolved in 0.5% SDS and adjustedto 0.5M NaCl. Poly A⁺ RNA was isolated with Dynabeads Oligo (dT)₂₅(Dynal A. S., Lake Success, N.Y.) according to the manufacturer'sprotocol. Poly A⁺ RNA was eluted from the beads and resuspended in TEbuffer. Twelve aliquots of 100 ng of RNA were reverse transcribed with aRT-PCR kit per the manufacturer's instructions (Boehringer Mannheim Cat.No. 1483-188) using a dT oligo for priming. For the heavy chain, PCRamplifications of 6 RNA/DNA hybrids were carried out for 25 cycles usinga murine IgG2a hinge primer (SEQ ID NO: 1) and a heavy chain signalsequence primer (SEQ ID NO: 2). Similarly, for the light chain, PCRamplificatons of 6 RNA/DNA hybrids were carried out for 25 cycles usinga murine kappa primer (SEQ ID NO: 3) and a degenerate light chain signalsequence primer (SEQ ID NO: 4). The PCR products from each of the 12amplifications were ligated in a PCR2000 vector (TA cloning Kit,Invitrogen, Cat. No. K2000-01). Colonies of recombinant clones wererandomly picked and minipreparations of plasmid DNA were prepared usingan alkaline extraction procedure described by Birnboim and Doly in Nucl.Acids Res. 7, 1513 (1979). The isolated plasmid DNA was digested withEcoRI and analyzed on a 0.8% agarose gel. Double-stranded cDNA insertsof the appropriate size, i.e., ˜700 bp for the heavy chain and ˜700 bpfor the light chain, were sequenced by a modification of the Sangermethod. The sequence of all 12 of the heavy and light chains werecompared to generate a consensus BC2 heavy chain variable regionsequence (SEQ ID NO: 5)and consensus BC2 light chain variable regionsequence (SEQ ID NO: 6).

Sequence analysis of the BC2 heavy chain variable region cDNA revealed a363 nucleotide open reading frame encoding a 121 amino acid sequence(SEQ ID NO: 7). The heavy chain CDR1, 2 and 3 sequences are listed inSEQ ID NOs: 8, 9 and 10, respectively.

Sequence analysis of the BC2 light chain variable region cDNA revealed a321 nucleotide open reading frame encoding a 107 amino acid sequence(SEQ ID NO: 11). The light chain CDR1, 2 and 3 sequences are listed inSEQ ID NOs: 12, 13 and 14, respectively.

EXAMPLE 6 Humanized Antibodies

Six humanized antibodies designated SB 249413, SB 249415, SB 249416,SB249417, SB 257731 and SB 257732 were designed to contain the murineCDRs described above in a human antibody framework.

SB 249413

SB 249413 contains the heavy chain F9HZHC 1-0 and the light chain F9HZLC1-0. The synthetic variable region humanized heavy chain F9HZHC 1-0 wasdesigned using the first three framework regions of the heavy chainobtained from immunoglobulin RF-TS3'CL (Capra, J. D. et al., J. Clin.Invest. 86, 1320-1328 (1990) identified in the Kabat database asKabpro:Hhc10w) and the BC2 heavy chain CDRs described previously. Noframework amino acids substitutions which might influence CDRpresentation were made. Four overlapping synthetic oligonucleotides weregenerated (SEQ ID NOs: 15, 16, 17 and 18) which, when annealed andextended, code for the amino acids representing the heavy chain variableregion through and including CDR3 (SEQ ID NOs: 19 and 20). Thissynthetic gene was then amplified using PCR primers (SEQ ID NOs: 21 and22) and ligated into the pCR2000 vector (TA cloning Kit, Invitrogen,Cat. No. K2000-01) and isolated from a SpeI, KpnI restriction digest. Asecond DNA fragment coding for the campath signal sequence including thefirst five amino acids of the variable region (SEQ ID NOs: 23 and 24)was made by PCR amplification of the appropriate region of a constructencoding a humanized anti-Respiratory Syncitial Virus heavy chain (SEQID NO: 25) with two primers (SEQ ID NOs: 26 and 27) and digesting withthe restriction enzymes EcoRI and SpeI. The two fragments generated wereligated into an EcoR1, KpnI digested pFHZHC2-6pCD mammalian cellexpression vector which contained the remainder of a human consensusframework 4 and IgG1 constant region. The vector contained a singleamino acid mutation of the pFHZHC2-3pCD vector described in publishedInternational Patent Application No. WO94/05690. The final residue offramework 2 (residue 49) was mutated from Ser to Ala by digestingpFHZHC2-3pCD with XbaI and EcoR5 and inserting a linker generated fromtwo synthetic oligonucleotides (SEQ ID NOs: 28 and 29). The sequence ofthe F9HZHC 1-0 insert is shown in SEQ ID NOs: 30 and 31.

The synthetic variable region humanized light chain F9HZLC 1-0 wasdesigned using the framework regions of the human light chain obtainedfrom immunoglobulin LS8'CL (Carmack et al., J. Exp. Med. 169, 1631-1643(1989) identified in the Kabat database as Kabpro:Hkl318) and the BC2light chain CDRs described previously. No framework amino acidssubstitutions which might influence CDR presentation were made. Twooverlapping synthetic oligonucleotides were generated (SEQ ID NOs: 32and 33) which, when annealed and extended, code for amino acidsrepresenting the light chain variable region (SEQ ID NOs: 34 and 35).This synthetic gene was then amplified using PCR primers (SEQ ID NOs: 36and 37) and ligated into the pCR2000 vector (TA cloning Kit, Invitrogen,Cat. No. K2000-01), and isolated from a ScaI, SacII restriction digest.A second DNA fragment coding for the campath signal sequence includingthe first two amino acids of the variable region (SEQ ID NOs: 38 and 39)was made by PCR amplification of the the appropriate region of aconstruct encoding a humanized anti-Respiratory Syncitial Virus heavychain (SEQ ID NO: 25) with the two primers (SEQ ID NOs: 26 and 40) anddigesting with the restriction enzymes EcoRI and ScaI. The two fragmentsgenerated were ligated into an EcoR1, SacII digested pFHzLC1-2pCNmammalian cell expression vector which contained the remainder of ahuman framework 4 and kappa constant region. The vector contained asingle amino acid mutation of the pFHZLC1-1pCN vector described inpublished International Patent Application No. WO94/05690. A framework 2residue was mutated from Ser to Pro by digesting pFHZLC1-pCN with SmaIand Kpn1 and inserting a linker generated from two syntheticoligonucleotides (SEQ ID NOs: 41 and 42). The sequence of the F9HZLC 1-0insert is shown in SEQ ID NOs: 43 and 44.

SB 249415

SB 249415 contains the heavy chain F9HZHC 1-1 and the light chain F9HZLC1-1. These heavy and light chain constructs are based on F9HZHC 1-0 andF9HZLC 1-0, respectively, however, they have framework amino acidsubstitutions which can influence CDR presentation.

F9HZHC 1-1 has three framework amino acid substitutions which mightinfluence CDR presentation. Two overlapping synthetic oligonucleotideswere generated (SEQ ID NOs: 45 and 46), which when annealed andextended, code for amino acids representing the altered portion of theheavy chain variable region altered (SEQ ID NOs: 47 and 48). Thissynthetic gene was then amplified using PCR primers (SEQ ID NOs: 49 and50), ligated into the pCR2000 vector (TA cloning Kit, Invitrogen, Cat.No. K2000-01) and isolated from a EcoNI, KpnI restriction digest. Thisfragment was ligated into EcoNI, KpnI digested F9HZHC1-0 (SEQ ID NO: 30)vector. The sequence of the F9HZHC 1-1 insert is shown in SEQ ID NOs: 51and 52.

F9HZLC 1-1 has four framework amino acids substitutions which caninfluence CDR presentation. Two synthetic oligonucleotides weregenerated (SEQ ID NOs: 53 and 54), which when annealed, have KpnI andBamHI cohesive ends, and code for amino acids representing the alteredportion of the light chain variable region (SEQ ID NO: 55). F9HZLC 1-0(SEQ ID NO: 43) was digested with the restriction enzymes KpnI and BamHIand ligated to the synthetic DNA. The sequence of the F9HZLC 1-1 insertis shown in SEQ ID NOs: 56 and 57.

SB 249416

SB 249416 contains the heavy chain F9HZHC 1-1 (described above) (SEQ IDNO: 52) and the light chain F9HZLC 1-2. The light chain construct isbased on F9HZLC 1-1, however, it has one additional framework amino acidsubstitution which can influence CDR presentation.

Two synthetic oligonucleotides were generated (SEQ ID NOs: 58 and 59),which when annealed, have BamHI and XbaI cohesive ends and code foramino acids representing the altered portion of the light chain variableregion (SEQ ID NO: 60). F9HZLC 1-1 (SEQ ID NO: 56) vector was digestedwith the restriction enzymes BamHI and XbaI and ligated to the syntheticDNA. The sequence of the F9HZLC 1-2 insert is shown in SEQ ID NOs: 61and 62.

SB 249417

SB 249417 contains the heavy chain F9HZHC 1-1 (described above) (SEQ IDNO: 52) and the light chain F9HZLC 2-0. A F9HZLC 2-0 synthetic variableregion humanized light chain was designed using the framework regions ofthe human light chain obtained from immunoglobulin REI (Palm andHilschmann, Z. Physiol. Chem. 354, 1651-1654 (1973) identified in theKabat database as Kabpro: HKL111) and the BC2 light chain CDRs describedpreviously. Five amino acid consensus human substitutions wereintroduced. Six framework amino acids murine substitutions which caninfluence CDR presentation were made. Two overlapping syntheticoligonucleotides were generated (SEQ ID NOs: 63 and 64) which, whenannealed and extended, code for amino acids representing the light chainvariable region (SEQ ID NOs: 65 and 66). This synthetic gene was thenamplified using PCR primers (SEQ ID NOs: 67 and 68), ligated into thepCR2000 vector (TA cloning Kit, Invitrogen, Cat. No. K2000-01) andisolated from a ScaI, SacII restriction digest. A second DNA fragmentcoding for the campath signal sequence including the first two aminoacids of the variable region (SEQ ID NO: 38) was made by PCRamplification of the the appropriate region of a construct encoding ahumanized anti-Respiratory Syncitial Virus heavy chain (SEQ ID NO: 25)with two primers (SEQ ID NOs: 26 and 69) and digesting with therestriction enzymes EcoRI and ScaI. A third DNA fragment encoding theremainder of a human framework 4 (SEQ ID NO: 70) and having SacII andNarI cohesive ends was generated by annealing two syntheticoligonucleotides (SEQ ID NOs: 71 and 72). F9HZLC 1-0 (SEQ ID NO: 43) wasdigested with the restriction enzymes EcoRI and NarI and ligated to thethree DNA fragments. The sequence of the F9HZLC 2-0 insert is shown inSEQ ID NOs: 73 and 74.

SB 257731

SB 257731 contains the heavy chain F9HZHC 1-1 (SEQ ID NO: 52) and thelight chain F9HZLC 1-3, a single amino acid mutation of F9HZLC 1-2 (SEQID NO: 62). F9HZLC 1-2 was PCR amplified with two primers (SEQ ID NOs:26 and 69) and digested with the restriction enzymes EcoRI and ScaI. A94 bp fragment (SEQ ID NOs: 75 and 76) was isolated. The fragment wasligated into EcoRI, ScaI digested F9HZLC 1-2 vector to produce the lightchain construct F9HZLC 1-3. The sequence of the F9HZLC 1-3 insert isshown in SEQ ID NOs: 77 and 78.

SB 257732

SB 257732 contains the synthetic variable region humanized heavy chainF9HZHC 3-0 and light chain F9HZLC 3-0. Four overlapping syntheticoligonucleotides were generated (SEQ ID NOs: 79, 80, 81 and 82) which,when annealed and extended, code for the amino acids representing theheavy chain variable region being altered (SEQ ID NOs: 83 and 84). Thissynthetic gene was then amplified using PCR primers (SEQ ID NOs: 85 and86), ligated into the pCR2000 vector (TA cloning Kit, Invitrogen, Cat.No. K2000-01) and isolated from a StuI, KpnI restriction digest. Theisolated fragment was ligated into StuI, KpnI digested F9HZHC1-1 (SEQ IDNO: 52) vector. This vector was then digested with EcoRI, SpeI to removethe signal sequence. A DNA fragment coding for the campath signalsequence (SEQ ID NO: 23) including the first five amino acids of thevariable region was made by PCR amplification of F9HZHC1-0 with twoprimers (SEQ ID NOs: 26 and 87) and digesting with the restrictionenzymes EcoRI and SpeI. The fragment generated was ligated into thevector. The sequence of the F9HZHC3-0 insert is shown in SEQ ID NOs: 88and 89.

Four overlapping synthetic oligonucleotides were generated (SEQ ID NOs:90, 91, 92 and 93) which, when annealed and extended, code for aminoacids representing the light chain variable region (SEQ ID NOs: 94 and95). This synthetic gene was then amplified using PCR primers (SEQ IDNOs: 96 and 97) and ligated into the pCR2000 vector (TA cloning Kit,Invitrogen, Cat. No. K2000-01), and isolated from a ScaI, NarIrestriction digest. The isolated fragment was ligated into ScaI, NarIdigested F9HZLC1-3 (SEQ ID NO: 77) vector. The sequence of the F9HZLC3-0insert is shown in SEQ ID NOs: 98 and 99.

The humanized anti-Factor IX mAbs were expressed in CHO cells. A DG-44cell line adapted for suspension growth in serum-free medium was grownin 100 ml of protein-free medium containing 1× nucleosides and 0.05% F68in 250 ml disposable sterile erlenmeyer flasks (Corning) on a Innova2100 platform shaker (New Brunswick Scientific) at 150 rpm at 37° C. ina 5% CO₂, 95% air humidified incubator. These cells were passaged at4×10⁵ cells/ml twice weekly. 15 ug each of the pCN-Lc-Light Chain andpCD-Hc-heavy chain vectors were linearized by digestion with Not1,co-precipitated under sterile conditions and resuspended in 50 ul of 1×TE buffer (10 mM Tris, 1 mM EDTA, pH 7.5). The DNA was electroporatedusing a Bio-Rad Gene Pulser (Bio-Rad Laboratories) into the Acc-098cells using the technique of Hensley et al. in J. Biol. Chem. 269,23949-23958 (1994). 1.2×10⁷ cells were washed once in 12.5 ml of icecold PBSucrose (PBS, 272 mM sucrose, 7 mM sodium phosphate pH 7.4, 1 mMMgCl₂), resuspended in 0.8 ml of PBS, added to 50 ul of the DNA solutionand incubated on ice for 15 min. The cells were pulsed at 380 V and 25microfarads, then incubated on ice for 10 min. Cells were plated into 96well culture plates at 5×10⁵ cells/plate in maintenance medium for 24 hrprior to selection. Cells were selected for resistance to 400 ug/ml G418(Geneticin, Life Technologies, Inc.) in maintenance medium. 24 hr priorto assay, the cells were fed with 150 ul of the maintenance medium.

Conditioned medium from individual colonies was assayed using anelectrochemiluminescence (ECL) detection method on an origen analyzer(IGEN, Inc.). See Yang et al., Biotechnology 12, 193-194 (1994).

All solutions necessary for the performance of the assays (assay buffer)and for the operation of the analyzer (cell cleaner) were obtained fromIGEN. The antibodies (anti-human IgG (g-chain specific), Sigma Chemicalsand F(ab')₂ Fragment to Human IgG (H+L), Kirkegaard & Perry LaboratoriesInc.) were labelled with TAG-NHS-ester (IGEN, Inc.) at a 7:1 molar ratioof TAG:protein, while the Protein A (Sigma) was labelled withBiotin-LC-Sulfo-NHS-ester (IGEN, Inc.) at a 20:1 molar ratioBiotin:protein, both according to IGEN's recommendations.Streptavidin-coated magnetic beads (M-280) were obtained from Dynal.

Immunoassays were performed using the following protocol: per sample, 50ul of the Streptavidin-coated beads (final concentration 600 ug/mldiluted in PBS, pH7.8, with 1.25% Tween) were mixed with 50 ulBiotin-Protein A (final concentration 1 ug/diluted in PBS, pH7.8, with1.25% Tween) and incubated at room temperature for 15 min withagitation, 50 ul of the TAG antibodies (a mixture with a finalconcentration of 1.25 ug/ml F(ab')₂ Fragment to Human IgG (H+L) and 0.25ug/ml Anti-Human IgG (g-chain specific) diluted in PBS, pH7.8, with1.25% Tween) were added, the solution was then added to 50 ul ofconditioned medium and incubated with agitation at room temperature for1 hr. 200 ul of assay buffer was added to the reaction mix and thesample analyzed on the Origen I analyzer to measure ECL. The resultsindicated that approximately 20-37% of the colonies assayed secrete over15 ng/ml of the antibody with an average expression of about 150 ng/ml.

Humanized anti-Factor IX mAbs were purified from the conditioned mediausing a Procep A capture step followed by ion-exchange chromatography toreduce the DNA burden. Procep A sorbent material (Bioprocessing Ltd.,Durham, England) was used to prepare a column with a 1:1 diameter toheight ratio. Clarified conditioned media was loaded onto the column atabout 150 cm/hr. The column was washed sequentially with phosphatebuffered saline (PBS), PBS containing 1 M NaCl, and finally with PBS.The bound material was recovered with 0.1 M acetic acid elution. Theeluate was adjusted to pH 5.5 and was diluted (1:4) with water. Thediluted solution was loaded onto an S-Sepharose column (2.5×13 cm) whichwas pre-equilibrated with 20 mM sodium acetate, pH 5.5 at 80 cm/hr. Thecolumn was washed with the acetate buffer until a steady baseline wasobtained and the bound protein was eluted with 20 mM sodium phosphate,pH 7.4 at 25 cm/hr. The eluted material was filtered with a 0.4 micronmembrane and stored at 4° C.

EXAMPLE 7 Mouse-Human Chimeric Antibody

100 ng of BC2 RNA were reverse transcribed with a RT-PCR kit per themanufacturer's instructions (Boehringer Mannheim Cat. No. 1483-188)using a dT oligo for priming, and PCR amplified with synthetic ScaI (SEQID NO: 100) and NarI (SEQ ID NO: 101) primers to produce the BC2 lightchain variable region with Sca1, Nar1 ends (SEQ ID NOs: 102 and 103).This DNA was ligated into ScaI, NarI digested F9HZHC1-3 (SEQ ID 77) anddigested with ScaI, NarI to produce a mouse-human chimeric light chainF9CHLC (SEQ ID NOs: 104 and 105).

100 ng of BC2 RNA were reverse transcribed with a RT-PCR kit per themanufacturer's instructions (Boehringer Mannheim Cat. No. 1483-188)using a dT oligo for priming, and PCR amplified with synthetic SpeI (SEQID NO: 106) and NheI (SEQ ID NO: 107) primers to produce the BC2 heavychain variable region with Spe1, Nhe1 ends (SEQ ID NOs: 108 and 109).The campath signal sequence was PCR amplified from the RSVHZ19 heavychain (SEQ ID NO: 25) with EcoRI (SEQ ID 26) and SpeI (SEQ ID 87)primers. These two DNA fragments were ligated into a EcoRI, NheIdigested IL4CHHCpcd vector described in published International PatentApplication No. WO95/07301, replacing the IL4 variable region with theBC2 Factor IX mouse variable region, to produce a mouse-human chimericheavy chain F9CHHC (SEQ ID Nos: 110 and 111).

Co-transfection and purification of the mouse-human chimeric antibodychαFIX was accomplished as described above for the humanized constructs.

EXAMPLE 8 Efficacy of Humanized Factor IX mAbs in Rat Thrombus Model

In order to evaluate the efficacy of humanized anti-Factor IX antibodiesin prevention of arterial thrombosis, the rat carotid artery thrombosismodel as described above in Example 3 was used. Baseline parameters wereestablished for carotid blood flow, arterial pressure, heart rate,vessel patency and activated partial thromboplastin time (aPTT). Fifteenminutes thereafter, carotid injury was effected for 10 minutes. Theparameters were determined 60 minutes after onset of carotid injury.Carotid thrombus was also extracted from the carotid artery and weighed.

All agents were administered intravenously 15 minutes before the onsetof carotid injury. The following treatments were examined and comparedto the anti-Factor IX mAb BC2.

1. Vehicle

2. chαFIX: 3 mg/kg bolus

3. SB 249413: 3 mg/kg bolus

4. SB 249415: 3 mg/kg bolus

5. SB 249416: 3 mg/kg bolus

6. SB 249417: 3 mg/kg bolus

7. SB 257731: 3 mg/kg bolus

8. Heparin: 60 units/kg bolus+2 units/kg/min infusion

The aPTT was used as the primary criterion for evaluation of efficacyversus bleeding liabilities of the anti-coagulant/thrombotic agents usedin the study. The results in FIG. 8 demonstrate that the humanizedFactor IX mAbs SB 249413, SB 249415, SB 249416, SB 249417 and SB 257731had a modest effect on aPTT at 3.0 mg/kg which is within the clinicalaccepted range.

The effect of the Factor IX mAbs on thrombus mass is shown in FIG. 9.The results indicate that all of the humanized mAbs are equallyeffective in reducing thrombus mass.

The studies conducted in the rat carotid thrombosis model clearlydemonstrate the efficacy of the humanized Factor IX mAbs in preventionof thrombosis in a highly thrombogenic arterial injury model. Mostnotably, the efficacy of all of the humanized Factor IX mAbs wasdemonstrated within the desired therapeutic anticoagulant target definedby the aPTT.

EXAMPLE 9 Antibody Biochemical and Biophysical Properties

The molecular mass of SB 249417 was determined by MALD-MS to be 148,000Da. Analytical ultracentrifugation of SB 249417 gave an identical value.In the presence of Factor IX plus Ca²⁺, the antibodies derived from BC 2sedimented with a mass of 248,000 Da corresponding to the combined massof the mAb and two molecules of Factor IX. No evidence of higher orderedaggregates was observed in the presence or absence of Factor IX.

The kinetics of Factor IX binding to SB 249417 was assessed by BIAcoreanalysis with antibody bound to an immobilized protein A surface.Recombinant human Factor IX (rhFIX, Genetics Institute) at 49 nM wasused and measurements performed in the presence of 5 mM Ca²⁺. Theinteraction was characterized by rapid association, kass=2.0×10⁵ M⁻¹ s⁻¹and relatively slow off-rate, kdiss=4.1×10⁻⁴ s⁻¹. The calculated K_(d)for Factor IX binding was 1.9 nM.

Table 1 summarizes the biophysical properties of SB 249417.

                  TABLE 1                                                         ______________________________________                                        Summary of the Biophysical Properties of SB 249417                              Isotype                IgG1, kappa                                          ______________________________________                                        Purity by SDS-PAGE   >95% (under reducing                                        conditions)                                                                  Molecular Weight                                                              Mass Spectrometry 148,000 Da                                                  Analytical Ultracentrifugation 148,000 Da                                     Stoichiometry of Factor IX Binding                                            Isothermal Titration Calorimetry 1.5 moles Factor                             IX: 1 mole mAb                                                                Factor IX Binding Affinity                                                    Isothermal Titration Calorimetry Kd = 4 nM at 25° C.                   Biosensor Kd = 2 nM                                                           Factor IX Binding Kinetics                                                    Biosensor k.sub.ass = 2.0 × 10.sup.5 M.sup.-1 s.sup.-1                   k.sub.diss = 4 × 10.sup.-4 s.sup.-1                                  ______________________________________                                    

Table 2 summarizes the factor IX binding properties of mAbs of thepresent invention. The calculated dissociation constants wereessentially identical within experimental error.

                  TABLE 2                                                         ______________________________________                                        Kinetics of Factor IX Binding to Anti-Factor IX mAbs                              mAb       k.sub.ass (M.sup.-1 s.sup.-1)                                                             k.sub.diss (s.sup.-1)                                                                calc. K.sub.D (nM)                           ______________________________________                                        SB 249417 2.0 × 10.sup.5                                                                      4.1 × 10.sup.-4                                                                  1.9                                              BC2 4.8 × 10.sup.5 9.1 × 10.sup.-4 1.9                            Chf9 2.4 × 10.sup.5 3.0 × 10.sup.-4 1.3                           SB 249413 6.5 × 10.sup.5 2.8 × 10.sup.-3 3.7-5.1                  SB 249415 7.5 × 10.sup.5 1.8 × 10.sup.-4 1.1-2.3                  SB 249416 5.2 × 10.sup.5 4.1 × 10.sup.-4 0.8                      SB 257731 9.2 × 10.sup.5 9.9 × 10.sup.-4 1.1                      SB 257732 1.1 × 10.sup.6 1.2 × 10.sup.-3 1.5                    ______________________________________                                    

The interactions between rhFIX and SB 249417, BC2 and other humanizedconstructs were characterized by titration microcalorimetry, whichmeasures binding interactions in solution from the intrinsic heat ofbinding. Nine injections of 106 uM FIX were made into the calorimetercontaining 2 uM mAb SB 249417. Binding was detected in the first 4injections as exothermic heats. At the last 5 injections the mAb bindingsites were saturated with FIX and only background heats of mixing wereobserved. The results indicated that the equivalence point occurred at amolar binding ratio near 2 FIX per mAb, as expected. Nonlinear leastsquares analysis of the data yield the binding affinity.

The rhFIX affinities of the mabs were measured over a range oftemperature from 34-44° C. in 10 mM HEPES, 10 mM CaCl₂, 150 mM NaCl, pH7.4. These data allow the affinity at 37° C. to be determined directlyand the affinity at 25° C. to be calculated from the van't Hoffequation. The data in Table 3 indicate that the affinities of SB 249417,BC2 and its other humanized constructs are within error (a factor of 2)the same.

                  TABLE 3                                                         ______________________________________                                        Titration Calorimetry Results for Anti-FIX mAbs                                                        Molar Binding                                          Ratio                                                                       mAb    Kd, nM at 25° C.                                                                    Kd, nM at 37° C.                                                                    FIX/mAb                                      ______________________________________                                        BC2    10           20           1.4                                            SB 6 12 1.9                                                                   249413                                                                        SB 3 7 1.7                                                                    249415                                                                        SB 4 12 1.5                                                                   249417                                                                        SB 4 9 1.8                                                                    257732                                                                      ______________________________________                                    

The mAbs SB 249413, SB 249415, SB 249417 and SB 257732 all exhibitedvery similar thermal stabilities by differential scanning calorimetry.Their unfolding Tms ranged from 70-75° C. indicating high stabilityagainst thermally induced denaturation.

EXAMPLE 10 Mechanism of Antibody-Mediated Inhibition of Factor IX

A library of chimeric constructs composed of sequences of Factor IXspliced into the framework of the homologous protein Factor VII wasconstructed and used to map the epitope for the Factor IX BC2 mAb. SeeCheung et al., Thromb. Res. 80, 419-427 (1995). Binding was measuredusing a BiaCore 2000 surface plasmon resonance device. The BC2 antibodywas coupled directly to the chip using the NHS/EDC reaction. Binding wasmeasured by 2 min of contact time at 20 uL/min with 200 nM of each ofthe given constructs in 25 mM MOPS, pH 7.4, 0.15 M NaCl, 5 mM CaCl₂.Dissociation was monitored for 3 min using the same buffer with noprotein. No binding was detected to the wild type construct in thepresence of 50 mM EDTA. The data are presented in Table 4.

                  TABLE 4                                                         ______________________________________                                        Summary of Binding of Factor IX Constructs to BC2                               Antibody                                                                          Construct         Degree of Binding                                     ______________________________________                                        Plasma IXa          Binds                                                       r-IX Binds                                                                    Plasma VII No Binding                                                         IX LC/VII HC Binds                                                            IX-A/VII Binds                                                                VII gla/IX No Binding                                                         VII-A/IX No Binding                                                           VII g1a (IX 3-11)/IX Binds                                                    VII g1a (IX 3-6)/IX Very Low Binding                                          VII g1a (IX 9-11)/IX Very Low Binding                                         IX K5A Binds                                                                ______________________________________                                    

These data indicate that the constructs containing the Factor IX lightchain and Factor VII heavy chain (IX LC/VII HC); the Factor IX gla andaromatic stack domains (IX-A/VII); residues 3-11 of Factor IX gla domainwithin the Factor VII gla domain (VII gla (IX 3-11)/IX); and Factor IXhaving a lysine to alanine substitution at residue 5 (IX K5A) exhibitbinding to BC2. The VII gla (IX 3-11)/IX construct exhibited BC2 bindingequivalent to wild type Factor IX (plasma IXa and r-IX). Thus, the BC2antibody binds to an epitope contained within residues 3-11 of theFactor IX gla domain.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof, and,accordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indicating the scope of theinvention.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 111                                         - -  - - (2) INFORMATION FOR SEQ ID NO:1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                               - - CATCCTAGAG TCACCGAGGA            - #                  - #                      - # 20                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                               - - AGCTGCCCAA AGTGCCCAAG C           - #                  - #                      - #21                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                               - - CTAACACTCA TTCCTGTTGA AGCTCTTGAC AATGGG      - #                  -     #       36                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                               - - GATTTTCARG TGCAGATTTT C           - #                  - #                      - #21                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 363 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                               - - CAGATCCAGT TGGTGCAGTC TGGACCTGAG CTGAAGAAGC CTGGAGAGAC AG -             #TCAAGATC     60                                                                 - - TCCTGCAAGG CTTCTGGGTA CACCTTCACA AACTATGGAA TGAACTGGGT GA -            #AGCAGGCT    120                                                                 - - CCAGGAAAGG GTTTAAAGTG GATGGGCTGG ATAAACACCA GAAATGGAAA GT -            #CAACATAT    180                                                                 - - GTTGATGACT TCAAGGGACG GTTTGCCTTC TCTTTGGAAA GCTCTGCCAG CA -            #CTGCCAAT    240                                                                 - - TTGCAGATCG ACAACCTCAA AGATGAGGAC ACGGCTACAT ATTTCTGTAC AA -            #GAGAAGGG    300                                                                 - - AATATGGATG GTTACTTCCC TTTTACTTAC TGGGGCCAAG GGACTCTGGT CA -            #CTGTCTCT    360                                                                 - - GCA                  - #                  - #                  - #                363                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                               - - CAAATTGTTC TCTCCCAGTC TCCAGCAATC CTGTCTGCAT CTCCAGGGGA GA -             #AGGTCACA     60                                                                 - - ATGACTTGCA GGGCCAGCTC AAGTGTAAAT TACATGCACT GGTACCAGCA GA -            #AGCCAGGA    120                                                                 - - TCCTCCCCCA AACCCTGGAT TTATGCCACA TCCAACCTGG CTTCTGGAGT CC -            #CTGCTCGC    180                                                                 - - TTCAGTGGCA GTGGGTCTGG GACCTCTTAC TCTCTCACAA TCAGCAGAGT GG -            #AGGCTGAA    240                                                                 - - GATGCTGCCA CTTATTACTG CCAGCAGTGG AGTATTAACC CACGGACGTT CG -            #GTGGAGGC    300                                                                 - - ACCAAGCTGG AAATCAAACG G           - #                  - #                     321                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 121 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                               - - Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Le - #u Lys Lys Pro Gly Glu       1               5  - #                10  - #                15               - - Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                  20      - #            25      - #            30                   - - Gly Met Asn Trp Val Lys Gln Ala Pro Gly Ly - #s Gly Leu Lys Trp Met              35          - #        40          - #        45                       - - Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe          50              - #    55              - #    60                           - - Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Se - #r Ala Ser Thr Ala Asn      65                  - #70                  - #75                  - #80        - - Leu Gln Ile Asp Asn Leu Lys Asp Glu Asp Th - #r Ala Thr Tyr Phe Cys                      85  - #                90  - #                95               - - Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                  100      - #           105      - #           110                  - - Gln Gly Thr Leu Val Thr Val Ser Ala                                              115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                               - - Asn Tyr Gly Met Asn                                                       1               5                                                             - -  - - (2) INFORMATION FOR SEQ ID NO:9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                               - - Trp Ile Asn Thr Arg Asn Gly Lys Ser Thr Ty - #r Val Asp Asp Phe Lys       1               5  - #                10  - #                15               - - Gly                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                              - - Glu Gly Asn Met Asp Gly Tyr Phe Pro Phe Th - #r Tyr                       1               5  - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                              - - Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Le - #u Ser Ala Ser Pro Gly       1               5  - #                10  - #                15               - - Glu Lys Val Thr Met Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                  20      - #            25      - #            30                   - - His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pr - #o Lys Pro Trp Ile Tyr              35          - #        40          - #        45                       - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser          50              - #    55              - #    60                           - - Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Se - #r Arg Val Glu Ala Glu      65                  - #70                  - #75                  - #80        - - Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                      85  - #                90  - #                95               - - Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Ar - #g                                      100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                              - - Arg Ala Ser Ser Ser Val Asn Tyr Met His                                   1               5  - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                              - - Ala Thr Ser Asn Leu Ala Ser                                               1               5                                                             - -  - - (2) INFORMATION FOR SEQ ID NO:14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                              - - Gln Gln Trp Ser Ile Asn Pro Arg Thr                                       1               5                                                             - -  - - (2) INFORMATION FOR SEQ ID NO:15:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 104 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                              - - CAACTAGTGC AATCTGGGTC TGAGTTGAAG AAGCCTGGGG CCTCAGTGAA GG -             #TTTCCTGC     60                                                                 - - AAGGCCTCTG GATACACCTT CACTAACTAT GGAATGAACT GGGT   - #                      - #104                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:16:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 108 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                              - - TTGAAGTCAT CAACATATGT TGACTTTCCA TTTCTGGTGT TTATCCATCC CA -             #TCCACTCG     60                                                                 - - AGCCCTTGTC CAGGGGCCTG TCGCACCCAG TTCATTCCAT AGTTAGTG  - #                   108                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:17:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                              - - GTCAACATAT GTTGATGACT TCAAGGGGCG GTTTGTCTTC CCTCTGTCAG CA -             #CGGCATAT     60                                                                 - - CTACAGATCA GCAGCCTAAA GGCTGACGAC ACTGCAGTGT ATTACTG   - #                   107                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:18:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 91 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                              - - GGTACCCTGG CCCCAGTAAG TAAAAGGGAA GTAACCATCC ATATTCCCTT CT -             #CTCGCACA     60                                                                 - - GTAATACACT GCAGTGTCGT CAGCCTTTAG G        - #                  - #              91                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:19:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 337 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 2...337                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                              - - A CTA GTG CAA TCT GGG TCT GAG TTG AAG AAG - #CCT GGG GCC TCA GTG        AAG     49                                                                        Leu Val Gln Ser Gly Ser Glu Leu Lys L - #ys Pro Gly Ala Ser Val Lys           1               - #5                  - #10                  - #15          - - GTT TCC TGC AAG GCC TCT GGA TAC ACC TTC AC - #T AAC TAT GGA ATG AAC           97                                                                       Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Th - #r Asn Tyr Gly Met Asn                       20      - #            25      - #            30                   - - TGG GTG CGA CAG GCC CCT GGA CAA GGG CTC GA - #G TGG ATG GGA TGG ATA          145                                                                       Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gl - #u Trp Met Gly Trp Ile                   35          - #        40          - #        45                       - - AAC ACC AGA AAT GGA AAG TCA ACA TAT GTT GA - #T GAC TTC AAG GGG CGG          193                                                                       Asn Thr Arg Asn Gly Lys Ser Thr Tyr Val As - #p Asp Phe Lys Gly Arg               50              - #    55              - #    60                           - - TTT GTC TTC TCC TTG GAC ACC TCT GTC AGC AC - #G GCA TAT CTA CAG ATC          241                                                                       Phe Val Phe Ser Leu Asp Thr Ser Val Ser Th - #r Ala Tyr Leu Gln Ile           65                  - #70                  - #75                  - #80        - - AGC AGC CTA AAG GCT GAC GAC ACT GCA GTG TA - #T TAC TGT GCG AGA GAA          289                                                                       Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Ty - #r Tyr Cys Ala Arg Glu                           85  - #                90  - #                95               - - GGG AAT ATG GAT GGT TAC TTC CCT TTT ACT TA - #C TGG GGC CAG GGT ACC          337                                                                       Gly Asn Met Asp Gly Tyr Phe Pro Phe Thr Ty - #r Trp Gly Gln Gly Thr                       100      - #           105      - #           110                  - -  - - (2) INFORMATION FOR SEQ ID NO:20:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 112 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                              - - Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pr - #o Gly Ala Ser Val Lys       1               5  - #                10  - #                15               - - Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Th - #r Asn Tyr Gly Met Asn                  20      - #            25      - #            30                   - - Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gl - #u Trp Met Gly Trp Ile              35          - #        40          - #        45                       - - Asn Thr Arg Asn Gly Lys Ser Thr Tyr Val As - #p Asp Phe Lys Gly Arg          50              - #    55              - #    60                           - - Phe Val Phe Ser Leu Asp Thr Ser Val Ser Th - #r Ala Tyr Leu Gln Ile      65                  - #70                  - #75                  - #80        - - Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Ty - #r Tyr Cys Ala Arg Glu                      85  - #                90  - #                95               - - Gly Asn Met Asp Gly Tyr Phe Pro Phe Thr Ty - #r Trp Gly Gln Gly Thr                  100      - #           105      - #           110                  - -  - - (2) INFORMATION FOR SEQ ID NO:21:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 33 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                              - - GCTACTAGTG CAATCTGGGT CTGAGTTGAA GCC       - #                  - #             33                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:22:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                              - - TGGGTACCCT GGCCCCAGTA AGTAAAAGGG         - #                  - #               30                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:23:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 97 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...95                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC TTC          53                                                                                          - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                          - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC CA - #G GTC CAA CTA GT               - # 97                                                                    Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #n Val Gln Leu                   10                  - #15                  - #20                               - -  - - (2) INFORMATION FOR SEQ ID NO:24:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                              - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr Gly       1               5  - #                10  - #                15               - - Val His Ser Gln Val Gln Leu                                                          20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:25:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 110 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                              - - GGAGACGCCA TCGAATTCTG AGCACACAGG ACCTCACCAT GGGATGGAGC TG -             #TATCATCC     60                                                                 - - TCTTCTTGGT AGCAACAGCT ACAGGTGTCC ACTCCCAGGT CCAACTGCAG  - #                 110                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:26:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                              - - GGAGACGCCA TCGAATTCTG A           - #                  - #                      - #21                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:27:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                              - - GATTGCACTA GTTGGACCTG GGAGTGGACA         - #                  - #               30                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:28:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 77 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                              - - CTAGAGTGGG TCGCAGAGAT CTCTGATGGT GGTAGTTACA CCTACTATCC AG -             #ACACTGTG     60                                                                 - - ACGGGCCGGT TCACGAT             - #                  - #                      - #   77                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:29:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 73 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                              - - ATCGTGAACC GGCCCGTCAC AGTGTCTGGA TAGTAGGTGT AACTACCACC AT -             #CAGAGATC     60                                                                 - - TCTGCGACCC ACT              - #                  - #                      - #      73                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:30:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 363 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...363                                                         (D) OTHER INFORMATION: - #F9HZHC 1-0                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                              - - CAG GTG CAA CTA GTG CAA TCT GGG TCT GAG TT - #G AAG AAG CCT GGG GCC           48                                                                       Gln Val Gln Leu Val Gln Ser Gly Ser Glu Le - #u Lys Lys Pro Gly Ala            1               5  - #                10  - #                15               - - TCA GTG AAG GTT TCC TGC AAG GCC TCT GGA TA - #C ACC TTC ACT AAC TAT           96                                                                       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                       20      - #            25      - #            30                   - - GGA ATG AAC TGG GTG CGA CAG GCC CCT GGA CA - #A GGG CTC GAG TGG ATG          144                                                                       Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gl - #n Gly Leu Glu Trp Met                   35          - #        40          - #        45                       - - GGA TGG ATA AAC ACC AGA AAT GGA AAG TCA AC - #A TAT GTT GAT GAC TTC          192                                                                       Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe               50              - #    55              - #    60                           - - AAG GGA CGG TTT GTC TTC TCC TTG GAC ACC TC - #T GTC AGC ACG GCA TAT          240                                                                       Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Se - #r Val Ser Thr Ala Tyr           65                  - #70                  - #75                  - #80        - - CTA CAG ATC AGC AGC CTA AAG GCT GAC GAC AC - #T GCA GTG TAT TAC TGT          288                                                                       Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Th - #r Ala Val Tyr Tyr Cys                           85  - #                90  - #                95               - - GCG AGA GAA GGG AAT ATG GAT GGT TAC TTC CC - #T TTT ACT TAC TGG GGC          336                                                                       Ala Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                       100      - #           105      - #           110                  - - CAG GGT ACC CTG GTC ACC GTC TCC TCA    - #                  - #                363                                                                     Gln Gly Thr Leu Val Thr Val Ser Ser                                                   115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:31:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 121 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                              - - Gln Val Gln Leu Val Gln Ser Gly Ser Glu Le - #u Lys Lys Pro Gly Ala       1               5  - #                10  - #                15               - - Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                  20      - #            25      - #            30                   - - Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gl - #n Gly Leu Glu Trp Met              35          - #        40          - #        45                       - - Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe          50              - #    55              - #    60                           - - Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Se - #r Val Ser Thr Ala Tyr      65                  - #70                  - #75                  - #80        - - Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Th - #r Ala Val Tyr Tyr Cys                      85  - #                90  - #                95               - - Ala Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                  100      - #           105      - #           110                  - - Gln Gly Thr Leu Val Thr Val Ser Ser                                              115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:32:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 165 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                              - - AGTACTGACA CAGTCTCCAG CCACCCTGTC TTTGTCTCCA GGGGAAAGAG CC -             #ACCCTCTC     60                                                                 - - CTGCAGGGCC AGCTCAAGTG TAAATTACAT GCACTGGTAC CAACAGAGAC CT -            #GGCCAGGC    120                                                                 - - TCCCAGGCTC CTCATCTATG CCACTAGTAA CCTGGCTTCT GGCAT   - #                     165                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:33:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 146 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                              - - CCGCGGGTTA ATACTCCACT GCTGACAGTA ATAAACCGCA AAATCTTCAG GC -             #TCTAGACT     60                                                                 - - GCTGATGGTG AGAGTGAAAT CTGTCCCAGA CCCGGATCCA CTGAACCTGG CT -            #GGGATGCC    120                                                                 - - AGAAGCCAGG TTACTAGTGG CATAGA          - #                  - #                 146                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:34:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 280 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 2...280                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                              - - A GTA CTG ACA CAG TCT CCA GCC ACC CTG TCT - #TTG TCT CCA GGG GAA        AGA     49                                                                        Val Leu Thr Gln Ser Pro Ala Thr Leu S - #er Leu Ser Pro Gly Glu Arg           1               - #5                  - #10                  - #15          - - GCC ACC CTC TCC TGC AGG GCC AGC TCA AGT GT - #A AAT TAC ATG CAC TGG           97                                                                       Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                       20      - #            25      - #            30                   - - TAC CAA CAG AGA CCT GGC CAG GCT CCC AGG CT - #C CTC ATC TAT GCC ACT          145                                                                       Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Le - #u Leu Ile Tyr Ala Thr                   35          - #        40          - #        45                       - - AGT AAC CTG GCT TCT GGC ATC CCA GCC AGG TT - #C AGT GGA TCC GGG TCT          193                                                                       Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Ph - #e Ser Gly Ser Gly Ser               50              - #    55              - #    60                           - - GGG ACA GAT TTC ACT CTC ACC ATC AGC AGT CT - #A GAG CCT GAA GAT TTT          241                                                                       Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Le - #u Glu Pro Glu Asp Phe           65                  - #70                  - #75                  - #80        - - GCG GTT TAT TAC TGT CAG CAG TGG AGT ATT AA - #C CCG CGG                  - #    280                                                                    Ala Val Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg                                       85  - #                90                                      - -  - - (2) INFORMATION FOR SEQ ID NO:35:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 93 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                              - - Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Le - #u Ser Pro Gly Glu Arg       1               5  - #                10  - #                15               - - Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                  20      - #            25      - #            30                   - - Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Le - #u Leu Ile Tyr Ala Thr              35          - #        40          - #        45                       - - Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Ph - #e Ser Gly Ser Gly Ser          50              - #    55              - #    60                           - - Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Le - #u Glu Pro Glu Asp Phe      65                  - #70                  - #75                  - #80        - - Ala Val Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg                                  85  - #                90                                      - -  - - (2) INFORMATION FOR SEQ ID NO:36:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                              - - TCGAGTACTG ACACAGTCTC CAGCCAC          - #                  - #                 27                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:37:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                              - - GACCGCGGGT TAATACTCCA CTGCTGA          - #                  - #                 27                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:38:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 94 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...92                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC TTC          53                                                                                          - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                          - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC GA - #G ATA GTA CT                 - #   94                                                                    Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #u Ile Val                       10                  - #15                  - #20                               - -  - - (2) INFORMATION FOR SEQ ID NO:39:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                              - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr Gly       1               5  - #                10  - #                15               - - Val His Ser Glu Ile Val                                                              20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:40:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                              - - GACTGTGTCA GTACTATCTC GGAGTGGACA         - #                  - #               30                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:41:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 55 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                              - - GGGCAGCCTC CTAAGTTGCT CATTTACTGG GCGTCGACTA GGGAATCTGG GG - #TAC              55                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:42:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                              - - CCCAGATTCC CTAGTCGACG CCCAGTAAAT GAGCAACTTA GGAGGCTGCC C - #                 51                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:43:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...321                                                         (D) OTHER INFORMATION: - #F9HZLC1-0                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                              - - GAA ATA GTA CTG ACA CAG TCT CCA GCC ACC CT - #G TCT TTG TCT CCA GGG           48                                                                       Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro Gly            1               5  - #                10  - #                15               - - GAA AGA GCC ACC CTC TCC TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAA CAG AGA CCT GGC CAG GCT CC - #C AGG CTC CTC ATC TAT          144                                                                       His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Arg Leu Leu Ile Tyr                   35          - #        40          - #        45                       - - GCC ACT AGT AAC CTG GCT TCT GGC ATC CCA GC - #C AGG TTC AGT GGA TCC          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Al - #a Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGG TCT GGG ACA GAT TTC ACT CTC ACC ATC AG - #C AGT CTA GAG CCT GAA          240                                                                       Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu           65                  - #70                  - #75                  - #80        - - GAT TTT GCG GTT TAT TAC TGT CAG CAG TGG AG - #T ATT AAC CCG CGG ACG          288                                                                       Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA CG - #A                  -      #        321                                                                    Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                           100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:44:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                              - - Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro        Gly                                                                               1               5 - #                 10 - #                 15             - - Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                   20     - #             25     - #             30                  - - His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Arg Leu Leu Ile Tyr               35         - #         40         - #         45                      - - Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Al - #a Arg Phe Ser Gly Ser           50             - #     55             - #     60                          - - Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu       65                 - # 70                 - # 75                 - # 80       - - Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                       85 - #                 90 - #                 95              - - Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                      100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:45:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 134 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                              - - CCTGGACAAG GGCTCAAGTG GATGGGATGG ATAAACACCA GAAATGGAAA GT -             #CAACATAT     60                                                                 - - GTTGATGACT TCAAGGGACG GTTTGTCTTC TCTCTAGACT CCTCTGTCAG CA -            #CGGCATAT    120                                                                 - - CTACAGATCA GCAG              - #                  - #                      - #    134                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:46:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 134 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                              - - GGTACCCTGG CCCCAGTAAG TAAAAGGGAA GTAACCATCC ATATTCCCTT CT -             #CTCGTACA     60                                                                 - - GTAATACACT GCAGTGTCGT CAGCCTTTAG GCTGCTGATC TGTAGATATG CC -            #GTGCTGAC    120                                                                 - - AGAGGAGTCT AGAG              - #                  - #                      - #    134                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:47:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 225 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...225                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                              - - CCT GGA CAA GGG CTC AAG TGG ATG GGA TGG AT - #A AAC ACC AGA AAT GGA           48                                                                       Pro Gly Gln Gly Leu Lys Trp Met Gly Trp Il - #e Asn Thr Arg Asn Gly            1               5  - #                10  - #                15               - - AAG TCA ACA TAT GTT GAT GAC TTC AAG GGA CG - #G TTT GTC TTC TCT CTA           96                                                                       Lys Ser Thr Tyr Val Asp Asp Phe Lys Gly Ar - #g Phe Val Phe Ser Leu                       20      - #            25      - #            30                   - - GAC TCC TCT GTC AGC ACG GCA TAT CTA CAG AT - #C AGC AGC CTA AAG GCT          144                                                                       Asp Ser Ser Val Ser Thr Ala Tyr Leu Gln Il - #e Ser Ser Leu Lys Ala                   35          - #        40          - #        45                       - - GAC GAC ACT GCA GTG TAT TAC TGT ACG AGA GA - #A GGG AAT ATG GAT GGT          192                                                                       Asp Asp Thr Ala Val Tyr Tyr Cys Thr Arg Gl - #u Gly Asn Met Asp Gly               50              - #    55              - #    60                           - - TAC TTC CCT TTT ACT TAC TGG GGC CAG GGT AC - #C                  -      #        225                                                                    Tyr Phe Pro Phe Thr Tyr Trp Gly Gln Gly Th - #r                               65                  - #70                  - #75                               - -  - - (2) INFORMATION FOR SEQ ID NO:48:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 75 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                              - - Pro Gly Gln Gly Leu Lys Trp Met Gly Trp Il - #e Asn Thr Arg Asn        Gly                                                                              1               5  - #                10  - #                15              - - Lys Ser Thr Tyr Val Asp Asp Phe Lys Gly Ar - #g Phe Val Phe Ser Leu                  20      - #            25      - #            30                   - - Asp Ser Ser Val Ser Thr Ala Tyr Leu Gln Il - #e Ser Ser Leu Lys Ala              35          - #        40          - #        45                       - - Asp Asp Thr Ala Val Tyr Tyr Cys Thr Arg Gl - #u Gly Asn Met Asp Gly          50              - #    55              - #    60                           - - Tyr Phe Pro Phe Thr Tyr Trp Gly Gln Gly Th - #r                          65                  - #70                  - #75                               - -  - - (2) INFORMATION FOR SEQ ID NO:49:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                              - - TTTCCTGGAC AAGGGCTCAA GTGGATG          - #                  - #                 27                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:50:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                              - - TTTGGTACCC TGGCCCCAGT AAGT          - #                  - #                    24                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:51:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 363 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...363                                                         (D) OTHER INFORMATION: - #F9HZHC 1-1                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                              - - CAG GTG CAA CTA GTG CAA TCT GGG TCT GAG TT - #G AAG AAG CCT GGG GCC           48                                                                       Gln Val Gln Leu Val Gln Ser Gly Ser Glu Le - #u Lys Lys Pro Gly Ala            1               5  - #                10  - #                15               - - TCA GTG AAG GTT TCC TGC AAG GCC TCT GGA TA - #C ACC TTC ACT AAC TAT           96                                                                       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                       20      - #            25      - #            30                   - - GGA ATG AAC TGG GTG CGA CAG GCC CCT GGA CA - #A GGG CTC AAG TGG ATG          144                                                                       Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gl - #n Gly Leu Lys Trp Met                   35          - #        40          - #        45                       - - GGA TGG ATA AAC ACC AGA AAT GGA AAG TCA AC - #A TAT GTT GAT GAC TTC          192                                                                       Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe               50              - #    55              - #    60                           - - AAG GGA CGG TTT GTC TTC TCT CTA GAC TCC TC - #T GTC AGC ACG GCA TAT          240                                                                       Lys Gly Arg Phe Val Phe Ser Leu Asp Ser Se - #r Val Ser Thr Ala Tyr           65                  - #70                  - #75                  - #80        - - CTA CAG ATC AGC AGC CTA AAG GCT GAC GAC AC - #T GCA GTG TAT TAC TGT          288                                                                       Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Th - #r Ala Val Tyr Tyr Cys                           85  - #                90  - #                95               - - ACG AGA GAA GGG AAT ATG GAT GGT TAC TTC CC - #T TTT ACT TAC TGG GGC          336                                                                       Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                       100      - #           105      - #           110                  - - CAG GGT ACC CTG GTC ACC GTC TCC TCA    - #                  - #                363                                                                     Gln Gly Thr Leu Val Thr Val Ser Ser                                                   115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:52:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 121 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                              - - Gln Val Gln Leu Val Gln Ser Gly Ser Glu Le - #u Lys Lys Pro Gly Ala        1               5 - #                 10 - #                 15              - - Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                   20     - #             25     - #             30                  - - Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gl - #n Gly Leu Lys Trp Met               35         - #         40         - #         45                      - - Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe           50             - #     55             - #     60                          - - Lys Gly Arg Phe Val Phe Ser Leu Asp Ser Se - #r Val Ser Thr Ala Tyr       65                 - # 70                 - # 75                 - # 80       - - Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Th - #r Ala Val Tyr Tyr Cys                       85 - #                 90 - #                 95              - - Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                  100      - #           105      - #           110                  - - Gln Gly Thr Leu Val Thr Val Ser Ser                                              115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:53:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 82 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                              - - CAACAGAGAC CTGGCCAGGC TCCCAAGCCC TGGATCTATG CCACGAGTAA CC -             #TGGCTAGC     60                                                                 - - GGCGTCCCAG CCAGGTTCAG TG           - #                  - #                     82                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:54:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 90 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                              - - GATCCACTGA ACCTGGCTGG GACGCCGCTA GCCAGGTTAC TCGTGGCATA GA -             #TCCAGGGC     60                                                                 - - TTGGGAGCCT GGCCAGGTCT CTGTTGGTAC         - #                  - #               90                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:55:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                              - - Gln Gln Arg Pro Gly Gln Ala Pro Lys Pro Tr - #p Ile Tyr Ala Thr Ser        1               5 - #                 10 - #                 15              - - Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Se - #r                                       20     - #             25                                         - -  - - (2) INFORMATION FOR SEQ ID NO:56:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...321                                                         (D) OTHER INFORMATION: - #F9HZLC 1-1                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                              - - GAA ATA GTA CTG ACA CAG TCT CCA GCC ACC CT - #G TCT TTG TCT CCA GGG           48                                                                       Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro Gly            1               5  - #                10  - #                15               - - GAA AGA GCC ACC CTC TCC TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAA CAG AGA CCT GGC CAG GCT CC - #C AAG CCC TGG ATC TAT          144                                                                       His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Lys Pro Trp Ile Tyr                   35          - #        40          - #        45                       - - GCC ACG AGT AAC CTG GCT AGC GGC GTC CCA GC - #C AGG TTC AGT GGA TCC          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGG TCT GGG ACA GAT TTC ACT CTC ACC ATC AG - #C AGT CTA GAG CCT GAA          240                                                                       Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu           65                  - #70                  - #75                  - #80        - - GAT TTT GCG GTT TAT TAC TGT CAG CAG TGG AG - #T ATT AAC CCG CGG ACG          288                                                                       Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA CG - #A                  -      #        321                                                                    Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                           100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:57:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                              - - Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro        Gly                                                                               1               5 - #                 10 - #                 15             - - Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                   20     - #             25     - #             30                  - - His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Lys Pro Trp Ile Tyr               35         - #         40         - #         45                      - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser           50             - #     55             - #     60                          - - Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu       65                 - # 70                 - # 75                 - # 80       - - Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                       85 - #                 90 - #                 95              - - Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                       100     - #            105                                        - -  - - (2) INFORMATION FOR SEQ ID NO:58:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 41 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                              - - GATCCGGGTC TGGGACAGAT TACACTCTCA CGATATCCAG T    - #                      - #   41                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:59:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 41 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                              - - CTAGACTGGA TATCGTGAGA GTGTAATCTG TCCCAGACCC G    - #                      - #   41                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:60:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                              - - Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Il - #e Ser Ser                    1               5 - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:61:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...321                                                         (D) OTHER INFORMATION: - #F9HZLC 1-2                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                              - - GAA ATA GTA CTG ACA CAG TCT CCA GCC ACC CT - #G TCT TTG TCT CCA GGG           48                                                                       Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro Gly            1               5  - #                10  - #                15               - - GAA AGA GCC ACC CTC TCC TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAA CAG AGA CCT GGC CAG GCT CC - #C AAG CCC TGG ATC TAT          144                                                                       His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Lys Pro Trp Ile Tyr                   35          - #        40          - #        45                       - - GCC ACG AGT AAC CTG GCT AGC GGC GTC CCA GC - #C AGG TTC AGT GGA TCC          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGG TCT GGG ACA GAT TAC ACT CTC ACG ATA TC - #C AGT CTA GAG CCT GAA          240                                                                       Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu           65                  - #70                  - #75                  - #80        - - GAT TTT GCG GTT TAT TAC TGT CAG CAG TGG AG - #T ATT AAC CCG CGG ACG          288                                                                       Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA CG - #A                  -      #        321                                                                    Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                           100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:62:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                              - - Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Le - #u Ser Leu Ser Pro        Gly                                                                               1               5 - #                 10 - #                 15             - - Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                   20     - #             25     - #             30                  - - His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pr - #o Lys Pro Trp Ile Tyr               35         - #         40         - #         45                      - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser           50             - #     55             - #     60                          - - Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Se - #r Ser Leu Glu Pro Glu       65                 - # 70                 - # 75                 - # 80       - - Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                       85 - #                 90 - #                 95              - - Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ar - #g                                      100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:63:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 165 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                              - - AGTACTCACC CAGAGCCCAA GCAGCCTGAG CGCCAGCGTG GGTGACAGAG TG -             #ACCATCAC     60                                                                 - - CTGCAGGGCC AGCTCAAGTG TAAATTACAT GCACTGGTAC CAGCAGAAGC CA -            #GGTAAGGC    120                                                                 - - TCCAAAGCCT TGGATCTACG CCACTAGTAA CCTGGCTTCT GGTGT   - #                     165                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:64:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 161 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                              - - CCGCGGGTTA ATACTCCACT GCTGGCAGTA GTAGGTGGCG ATATCCTCTG GC -             #TGGAGGCT     60                                                                 - - GCTGATGGTG AAGGTGTAGT CTGTACCGCT ACCGGATCCG CTGAATCTGC TT -            #GGCACACC    120                                                                 - - AGAAGCCAGG TTACTAGTGG CGTAGATCCA AGGCTTTGGA G    - #                      - #  161                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:65:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 280 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 2...280                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                              - - A GTA CTC ACC CAG AGC CCA AGC AGC CTG AGC - #GCC AGC GTG GGT GAC        AGA     49                                                                        Val Leu Thr Gln Ser Pro Ser Ser Leu S - #er Ala Ser Val Gly Asp Arg           1               - #5                  - #10                  - #15          - - GTG ACC ATC ACC TGC AGG GCC AGC TCA AGT GT - #A AAT TAC ATG CAC TGG           97                                                                       Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                       20      - #            25      - #            30                   - - TAC CAG CAG AAG CCA GGT AAG GCT CCA AAG CC - #T TGG ATC TAC GCC ACT          145                                                                       Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pr - #o Trp Ile Tyr Ala Thr                   35          - #        40          - #        45                       - - AGT AAC CTG GCT TCT GGT GTG CCA AGC AGA TT - #C AGC GGA TCC GGT AGC          193                                                                       Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Ph - #e Ser Gly Ser Gly Ser               50              - #    55              - #    60                           - - GGT ACA GAC TAC ACC TTC ACC ATC AGC AGC CT - #C CAG CCA GAG GAT ATC          241                                                                       Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Le - #u Gln Pro Glu Asp Ile           65                  - #70                  - #75                  - #80        - - GCC ACC TAC TAC TGC CAG CAG TGG AGT ATT AA - #C CCG CGG                  - #    280                                                                    Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg                                       85  - #                90                                      - -  - - (2) INFORMATION FOR SEQ ID NO:66:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 93 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                              - - Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Al - #a Ser Val Gly Asp Arg       1               5  - #                10  - #                15               - - Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                  20      - #            25      - #            30                   - - Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pr - #o Trp Ile Tyr Ala Thr              35          - #        40          - #        45                       - - Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Ph - #e Ser Gly Ser Gly Ser          50              - #    55              - #    60                           - - Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Le - #u Gln Pro Glu Asp Ile      65                  - #70                  - #75                  - #80        - - Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg                                  85  - #                90                                      - -  - - (2) INFORMATION FOR SEQ ID NO:67:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                              - - TTTAGTACTC ACCCAGAGCC CAAGCAG          - #                  - #                 27                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:68:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 27 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                              - - TTCCGCGGGT TAATACTCCA CTGCTGG          - #                  - #                 27                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:69:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 33 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                              - - CTCGAGCAGT ACTATCTGGG AGTGGACACC TGT       - #                  - #             33                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:70:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: N-terminal                                        - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                              - - Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Il - #e Lys Arg Thr Val Ala       1               5  - #                10  - #                15               - - Ala                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:71:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                              - - GGACGTTCGG CCAAGGGACC AAGGTGGAAA TCAAACGGAC TGTGGCGG  - #                    48                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:72:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 52 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                              - - CGCCGCCACA GTCCGTTTGA TTTCCACCTT GGTCCCTTGG CCGAACGTCC GC - #                 52                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:73:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...321                                                         (D) OTHER INFORMATION: - #F9HZLC 2-0                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                              - - CAG ATA GTA CTC ACC CAG AGC CCA AGC AGC CT - #G AGC GCC AGC GTG GGT           48                                                                       Gln Ile Val Leu Thr Gln Ser Pro Ser Ser Le - #u Ser Ala Ser Val Gly            1               5  - #                10  - #                15               - - GAC AGA GTG ACC ATC ACC TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAG CAG AAG CCA GGT AAG GCT CC - #A AAG CCT TGG ATC TAC          144                                                                       His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pr - #o Lys Pro Trp Ile Tyr                   35          - #        40          - #        45                       - - GCC ACT AGT AAC CTG GCT TCT GGT GTG CCA AG - #C AGA TTC AGC GGA TCC          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Se - #r Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGT AGC GGT ACA GAC TAC ACC TTC ACC ATC AG - #C AGC CTC CAG CCA GAG          240                                                                       Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Se - #r Ser Leu Gln Pro Glu           65                  - #70                  - #75                  - #80        - - GAT ATC GCC ACC TAC TAC TGC CAG CAG TGG AG - #T ATT AAC CCG CGG ACG          288                                                                       Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGC CAA GGG ACC AAG GTG GAA ATC AAA CG - #G                  -      #        321                                                                    Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ar - #g                                           100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:74:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 107 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                              - - Gln Ile Val Leu Thr Gln Ser Pro Ser Ser Le - #u Ser Ala Ser Val        Gly                                                                               1               5 - #                 10 - #                 15             - - Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                   20     - #             25     - #             30                  - - His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pr - #o Lys Pro Trp Ile Tyr               35         - #         40         - #         45                      - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Se - #r Arg Phe Ser Gly Ser           50             - #     55             - #     60                          - - Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Se - #r Ser Leu Gln Pro Glu       65                 - # 70                 - # 75                 - # 80       - - Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                       85 - #                 90 - #                 95              - - Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ar - #g                                       100     - #            105                                        - -  - - (2) INFORMATION FOR SEQ ID NO:75:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 94 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...94                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC TTC          53                                                                                          - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                          - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC CA - #G ATA GTA CT                 - #   94                                                                    Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #n Ile Val Leu                   10                  - #15                  - #20                               - -  - - (2) INFORMATION FOR SEQ ID NO:76:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                              - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr Gly       1               5  - #                10  - #                15               - - Val His Ser Gln Ile Val Leu                                                          20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:77:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 401 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...401                                                        (D) OTHER INFORMATION: - #F9HZLC 1-3                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC TTC          53                                                                                          - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                          - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC CA - #G ATA GTA CTG ACA CAG          101                                                                       Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #n Ile Val Leu Thr Gln           10                  - #15                  - #20                  - #25        - - TCT CCA GCC ACC CTG TCT TTG TCT CCA GGG GA - #A AGA GCC ACC CTC TCC          149                                                                       Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Gl - #u Arg Ala Thr Leu Ser                           30  - #                35  - #                40               - - TGC AGG GCC AGC TCA AGT GTA AAT TAC ATG CA - #C TGG TAC CAA CAG AGA          197                                                                       Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Hi - #s Trp Tyr Gln Gln Arg                       45      - #            50      - #            55                   - - CCT GGC CAG GCT CCC AAG CCC TGG ATC TAT GC - #C ACG AGT AAC CTG GCT          245                                                                       Pro Gly Gln Ala Pro Lys Pro Trp Ile Tyr Al - #a Thr Ser Asn Leu Ala                   60          - #        65          - #        70                       - - AGC GGC GTC CCA GCC AGG TTC AGT GGA TCC GG - #G TCT GGG ACA GAT TAC          293                                                                       Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gl - #y Ser Gly Thr Asp Tyr               75              - #    80              - #    85                           - - ACT CTC ACG ATA TCC AGT CTA GAG CCT GAA GA - #T TTT GCG GTT TAT TAC          341                                                                       Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu As - #p Phe Ala Val Tyr Tyr           90                  - #95                  - #100                 - #105       - - TGT CAG CAG TGG AGT ATT AAC CCG CGG ACG TT - #C GGC GGA GGG ACC AAG          389                                                                       Cys Gln Gln Trp Ser Ile Asn Pro Arg Thr Ph - #e Gly Gly Gly Thr Lys                           110  - #               115  - #               120              - - GTG GAG ATC AAA            - #                  - #                      - #      401                                                                  Val Glu Ile Lys                                                                           125                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:78:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 125 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                              - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr Gly       1               5  - #                10  - #                15               - - Val His Ser Gln Ile Val Leu Thr Gln Ser Pr - #o Ala Thr Leu Ser Leu                  20      - #            25      - #            30                   - - Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ar - #g Ala Ser Ser Ser Val              35          - #        40          - #        45                       - - Asn Tyr Met His Trp Tyr Gln Gln Arg Pro Gl - #y Gln Ala Pro Lys Pro          50              - #    55              - #    60                           - - Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gl - #y Val Pro Ala Arg Phe      65                  - #70                  - #75                  - #80        - - Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Le - #u Thr Ile Ser Ser Leu                      85  - #                90  - #                95               - - Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gl - #n Gln Trp Ser Ile Asn                  100      - #           105      - #           110                  - - Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Gl - #u Ile Lys                          115          - #       120          - #       125                      - -  - - (2) INFORMATION FOR SEQ ID NO:79:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 81 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                              - - AGGCCTCTGG ATACACCTTC ACTAACTATG GAATGAACTG GGTGCGACAG GC -             #CCCTGGAC     60                                                                 - - AAGGGCTCGA GTGGATGGGA T           - #                  - #                      - #81                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:80:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                              - - TGTCTAGAGA GAAGACAAAC CGTCCCTTGA AGTCATCAAC ATATGTTGAC TT -             #TCCATTTC     60                                                                 - - TGGTGTTTAT CCATCCCATC CACTCGAGCC CTTGTCCAG      - #                      - #    99                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:81:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 87 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                              - - GGTTTGTCTT CTCTCTAGAC ACCTCTGTCA GCACGGCATA TCTACAGATC AG -             #CAGCCTAA     60                                                                 - - AGGCTGAGGA CACTGCAGTG TATTTCT          - #                  - #                 87                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:82:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 86 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                              - - GGTACCCTGG CCCCAGTAAG TAAAAGGGAA GTAACCATCC ATATTCCCTT CT -             #CTCGTACA     60                                                                 - - GAAATACACT GCAGTGTCCT CAGCCT          - #                  - #                  86                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:83:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 278 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 3...278                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                              - - AG GCC TCT GGA TAC ACC TTC ACT AAC TAT GGA - # ATG AAC TGG GTG CGA            47                                                                          Ala Ser Gly Tyr Thr Phe Thr Asn Tyr - #Gly Met Asn Trp Val Arg                 1              - # 5                 - # 10                 - # 15         - - CAG GCC CCT GGA CAA GGG CTC GAG TGG ATG GG - #A TGG ATA AAC ACC AGA           95                                                                       Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gl - #y Trp Ile Asn Thr Arg                           20  - #                25  - #                30               - - AAT GGA AAG TCA ACA TAT GTT GAT GAC TTC AA - #G GGA CGG TTT GTC TTC          143                                                                       Asn Gly Lys Ser Thr Tyr Val Asp Asp Phe Ly - #s Gly Arg Phe Val Phe                       35      - #            40      - #            45                   - - TCT CTA GAC ACC TCT GTC AGC ACG GCA TAT CT - #A CAG ATC AGC AGC CTA          191                                                                       Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr Le - #u Gln Ile Ser Ser Leu                   50          - #        55          - #        60                       - - AAG GCT GAG GAC ACT GCA GTG TAT TTC TGT AC - #G AGA GAA GGG AAT ATG          239                                                                       Lys Ala Glu Asp Thr Ala Val Tyr Phe Cys Th - #r Arg Glu Gly Asn Met               65              - #    70              - #    75                           - - GAT GGT TAC TTC CCT TTT ACT TAC TGG GGC CA - #G GGT ACC                  - #    278                                                                    Asp Gly Tyr Phe Pro Phe Thr Tyr Trp Gly Gl - #n Gly Thr                       80                  - #85                  - #90                               - -  - - (2) INFORMATION FOR SEQ ID NO:84:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 92 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                              - - Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Me - #t Asn Trp Val Arg Gln       1               5  - #                10  - #                15               - - Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tr - #p Ile Asn Thr Arg Asn                  20      - #            25      - #            30                   - - Gly Lys Ser Thr Tyr Val Asp Asp Phe Lys Gl - #y Arg Phe Val Phe Ser              35          - #        40          - #        45                       - - Leu Asp Thr Ser Val Ser Thr Ala Tyr Leu Gl - #n Ile Ser Ser Leu Lys          50              - #    55              - #    60                           - - Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr Ar - #g Glu Gly Asn Met Asp      65                  - #70                  - #75                  - #80        - - Gly Tyr Phe Pro Phe Thr Tyr Trp Gly Gln Gl - #y Thr                                      85  - #                90                                      - -  - - (2) INFORMATION FOR SEQ ID NO:85:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                              - - AGGCCTCTGG ATACACCTTC ACTAACTATG         - #                  - #               30                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:86:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                              - - GGTACCCTGG CCCCAGTAAG TAAAAG          - #                  - #                  26                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:87:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 37 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                              - - CCAGACTCGA CTAGTTGGAT CTGGGAGTGG ACACCTG      - #                       - #      37                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:88:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 446 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...446                                                        (D) OTHER INFORMATION: - #F9HZHC 3-0                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC        TTC      53                                                                                       - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                         - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC CA - #G ATC CAA CTA GTG CAA          101                                                                       Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #n Ile Gln Leu Val Gln           10                  - #15                  - #20                  - #25        - - TCT GGG TCT GAG TTG AAG AAG CCT GGG GCC TC - #A GTG AAG GTT TCC TGC          149                                                                       Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala Se - #r Val Lys Val Ser Cys                           30  - #                35  - #                40               - - AAG GCC TCT GGA TAC ACC TTC ACT AAC TAT GG - #A ATG AAC TGG GTG CGA          197                                                                       Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gl - #y Met Asn Trp Val Arg                       45      - #            50      - #            55                   - - CAG GCC CCT GGA CAA GGG CTC GAG TGG ATG GG - #A TGG ATA AAC ACC AGA          245                                                                       Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gl - #y Trp Ile Asn Thr Arg                   60          - #        65          - #        70                       - - AAT GGA AAG TCA ACA TAT GTT GAT GAC TTC AA - #G GGA CGG TTT GTC TTC          293                                                                       Asn Gly Lys Ser Thr Tyr Val Asp Asp Phe Ly - #s Gly Arg Phe Val Phe               75              - #    80              - #    85                           - - TCT CTA GAC ACC TCT GTC AGC ACG GCA TAT CT - #A CAG ATC AGC AGC CTA          341                                                                       Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr Le - #u Gln Ile Ser Ser Leu           90                  - #95                  - #100                 - #105       - - AAG GCT GAG GAC ACT GCA GTG TAT TTC TGT AC - #G AGA GAA GGG AAT ATG          389                                                                       Lys Ala Glu Asp Thr Ala Val Tyr Phe Cys Th - #r Arg Glu Gly Asn Met                           110  - #               115  - #               120              - - GAT GGT TAC TTC CCT TTT ACT TAC TGG GGC CA - #G GGT ACC CTG GTC ACC          437                                                                       Asp Gly Tyr Phe Pro Phe Thr Tyr Trp Gly Gl - #n Gly Thr Leu Val Thr                       125      - #           130      - #           135                  - - GTC TCC TCT              - #                  - #                       - #        446                                                                  Val Ser Ser                                                                           140                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO:89:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 140 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                               - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr        Gly                                                                              1               5  - #                10  - #                15              - - Val His Ser Gln Ile Gln Leu Val Gln Ser Gl - #y Ser Glu Leu Lys Lys                  20      - #            25      - #            30                   - - Pro Gly Ala Ser Val Lys Val Ser Cys Lys Al - #a Ser Gly Tyr Thr Phe              35          - #        40          - #        45                       - - Thr Asn Tyr Gly Met Asn Trp Val Arg Gln Al - #a Pro Gly Gln Gly Leu          50              - #    55              - #    60                           - - Glu Trp Met Gly Trp Ile Asn Thr Arg Asn Gl - #y Lys Ser Thr Tyr Val      65                  - #70                  - #75                  - #80        - - Asp Asp Phe Lys Gly Arg Phe Val Phe Ser Le - #u Asp Thr Ser Val Ser                      85  - #                90  - #                95               - - Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Al - #a Glu Asp Thr Ala Val                  100      - #           105      - #           110                  - - Tyr Phe Cys Thr Arg Glu Gly Asn Met Asp Gl - #y Tyr Phe Pro Phe Thr              115          - #       120          - #       125                      - - Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Se - #r Ser                          130              - #   135              - #   140                          - -  - - (2) INFORMATION FOR SEQ ID NO:90:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 90 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                         - - AGTACTGACA CAGTCTCCAT CCTCCCTGTC TGCATCTGTT GGGGACAGAG TC -             #ACCATCAC     60                                                                 - - TTGCAGGGCC AGCTCAAGTG TAAATTACAT         - #                  - #               90                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:91:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 108 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                              - - CTTGATGGGA CGCCGCTAGC CAGGTTACTC GTGGCATAGA TCCAGGGCTT GG -             #GAGCTTTG     60                                                                 - - CCAGGTTTCT GTTGGTACCA GTGCATGTAA TTTACACTTG AGCTGGCC  - #                   108                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:92:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 108 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                              - - TAACCTGGCT AGCGGCGTCC CATCAAGGTT CAGTGGATCC GGGTCTGGGA CA -             #GATTACAC     60                                                                 - - TCTCACGATA TCCAGTCTAC AACCTGAAGA TTTTGCGACT TATTACTG  - #                   108                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:93:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 102 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                              - - GGCGCCGCCA CAGTTCGTTT GATCTCCAGC TTGGTCCCTC CGCCGAACGT CC -             #GCGGGTTA     60                                                                 - - ATACTCCACT GCTGACAGTA ATAAGTCGCA AAATCTTCAG GT    - #                      - # 102                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:94:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 330 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 2...328                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                              - - A GTA CTG ACA CAG TCT CCA TCC TCC CTG TCT - #GCA TCT GTT GGG GAC        AGA     49                                                                        Val Leu Thr Gln Ser Pro Ser Ser Leu S - #er Ala Ser Val Gly Asp Arg           1               - #5                  - #10                  - #15          - - GTC ACC ATC ACT TGC AGG GCC AGC TCA AGT GT - #A AAT TAC ATG CAC TGG           97                                                                       Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                       20      - #            25      - #            30                   - - TAC CAA CAG AAA CCT GGC AAA GCT CCC AAG CC - #C TGG ATC TAT GCC ACG          145                                                                       Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pr - #o Trp Ile Tyr Ala Thr                   35          - #        40          - #        45                       - - AGT AAC CTG GCT AGC GGC GTC CCA TCA AGG TT - #C AGT GGA TCC GGG TCT          193                                                                       Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Ph - #e Ser Gly Ser Gly Ser               50              - #    55              - #    60                           - - GGG ACA GAT TAC ACT CTC ACG ATA TCC AGT CT - #A CAA CCT GAA GAT TTT          241                                                                       Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Le - #u Gln Pro Glu Asp Phe           65                  - #70                  - #75                  - #80        - - GCG ACT TAT TAC TGT CAG CAG TGG AGT ATT AA - #C CCG CGG ACG TTC GGC          289                                                                       Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg Thr Phe Gly                           85  - #                90  - #                95               - - GGA GGG ACC AAG CTG GAG ATC AAA CGA ACT GT - #G GCG GCG CC                 - #  330                                                                    Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Va - #l Ala Ala                                   100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:95:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 109 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                              - - Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Al - #a Ser Val Gly Asp Arg       1               5  - #                10  - #                15               - - Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Va - #l Asn Tyr Met His Trp                  20      - #            25      - #            30                   - - Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pr - #o Trp Ile Tyr Ala Thr              35          - #        40          - #        45                       - - Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Ph - #e Ser Gly Ser Gly Ser          50              - #    55              - #    60                           - - Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Le - #u Gln Pro Glu Asp Phe      65                  - #70                  - #75                  - #80        - - Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ile As - #n Pro Arg Thr Phe Gly                      85  - #                90  - #                95               - - Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Va - #l Ala Ala                              100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:96:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                              - - CAAGTACTGA CACAGTCTCC ATCCTC          - #                  - #                  26                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:97:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                              - - AGGGCGCCGC CACAGTTCGT TTGATC          - #                  - #                  26                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:98:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 412 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 27...412                                                        (D) OTHER INFORMATION: - #F9HZLC 3-0                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                              - - GAATTCTGAG CACACAGGAC CTCACC ATG GGA TGG AGC TGT - #ATC ATC CTC TTC          53                                                                                          - #           Met Gly Trp Ser - #Cys Ile Ile Leu Phe                          - #            1      - #         5                          - - TTG GTA GCA ACA GCT ACA GGT GTC CAC TCC CA - #G ATA GTA CTG ACA CAG          101                                                                       Leu Val Ala Thr Ala Thr Gly Val His Ser Gl - #n Ile Val Leu Thr Gln           10                  - #15                  - #20                  - #25        - - TCT CCA TCC TCC CTG TCT GCA TCT GTT GGG GA - #C AGA GTC ACC ATC ACT          149                                                                       Ser Pro Ser Ser Leu Ser Ala Ser Val Gly As - #p Arg Val Thr Ile Thr                           30  - #                35  - #                40               - - TGC AGG GCC AGC TCA AGT GTA AAT TAC ATG CA - #C TGG TAC CAA CAG AAA          197                                                                       Cys Arg Ala Ser Ser Ser Val Asn Tyr Met Hi - #s Trp Tyr Gln Gln Lys                       45      - #            50      - #            55                   - - CCT GGC AAA GCT CCC AAG CCC TGG ATC TAT GC - #C ACG AGT AAC CTG GCT          245                                                                       Pro Gly Lys Ala Pro Lys Pro Trp Ile Tyr Al - #a Thr Ser Asn Leu Ala                   60          - #        65          - #        70                       - - AGC GGC GTC CCA TCA AGG TTC AGT GGA TCC GG - #G TCT GGG ACA GAT TAC          293                                                                       Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gl - #y Ser Gly Thr Asp Tyr               75              - #    80              - #    85                           - - ACT CTC ACG ATA TCC AGT CTA CAA CCT GAA GA - #T TTT GCG ACT TAT TAC          341                                                                       Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu As - #p Phe Ala Thr Tyr Tyr           90                  - #95                  - #100                 - #105       - - TGT CAG CAG TGG AGT ATT AAC CCG CGG ACG TT - #C GGC GGA GGG ACC AAG          389                                                                       Cys Gln Gln Trp Ser Ile Asn Pro Arg Thr Ph - #e Gly Gly Gly Thr Lys                           110  - #               115  - #               120              - - CTG GAG ATC AAA CGA ACT GTG GC      - #                  - #                   412                                                                     Leu Glu Ile Lys Arg Thr Val Val                                                           125                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:99:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 129 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                              - - Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Va - #l Ala Thr Ala Thr Gly       1               5  - #                10  - #                15               - - Val His Ser Gln Ile Val Leu Thr Gln Ser Pr - #o Ser Ser Leu Ser Ala                  20      - #            25      - #            30                   - - Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ar - #g Ala Ser Ser Ser Val              35          - #        40          - #        45                       - - Asn Tyr Met His Trp Tyr Gln Gln Lys Pro Gl - #y Lys Ala Pro Lys Pro          50              - #    55              - #    60                           - - Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gl - #y Val Pro Ser Arg Phe      65                  - #70                  - #75                  - #80        - - Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Le - #u Thr Ile Ser Ser Leu                      85  - #                90  - #                95               - - Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gl - #n Gln Trp Ser Ile Asn                  100      - #           105      - #           110                  - - Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Gl - #u Ile Lys Arg Thr Val              115          - #       120          - #       125                      - - Val                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:100:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                             - - CAAATAGTAC TCTCCCAGTC TCCAGC          - #                  - #                  26                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:101:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 41 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                             - - GGATAAGCTT GGCGCCGCAA CAGTCGGTTT GATTTCCAGC T    - #                      - #   41                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:102:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 335 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...335                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                             - - CAG ATA GTA CTC TCC CAG TCT CCA GCA ATC CT - #G TCT GCA TCT CCA GGG           48                                                                       Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Le - #u Ser Ala Ser Pro Gly            1               5  - #                10  - #                15               - - GAG AAG GTC ACA ATG ACT TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Glu Lys Val Thr Met Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAG CAG AAG CCA GGA TCC TCC CC - #C AAA CCC TGG ATT TAT          144                                                                       His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pr - #o Lys Pro Trp Ile Tyr                   35          - #        40          - #        45                       - - GCC ACA TCC AAC CTG GCT TCT GGA GTC CCT GC - #T CGC TTC AGT GGC AGT          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGG TCT GGG ACC TCT TAC TCT CTC ACA ATC AG - #C AGA GTG GAG GCT GAA          240                                                                       Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Se - #r Arg Val Glu Ala Glu           65                  - #70                  - #75                  - #80        - - GAT GCT GCC ACT TAT TAC TGC CAG CAG TGG AG - #T ATT AAC CCA CGG ACG          288                                                                       Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGT GGA GGC ACC AAG CTG GAA ATC AAA CG - #G ACT GTT GCG GCG CC           335                                                                       Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Ar - #g Thr Val Ala Ala Pro                       100      - #           105      - #           110                  - -  - - (2) INFORMATION FOR SEQ ID NO:103:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 112 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                             - - Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Le - #u Ser Ala Ser Pro Gly       1               5  - #                10  - #                15               - - Glu Lys Val Thr Met Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                  20      - #            25      - #            30                   - - His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pr - #o Lys Pro Trp Ile Tyr              35          - #        40          - #        45                       - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser          50              - #    55              - #    60                           - - Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Se - #r Arg Val Glu Ala Glu      65                  - #70                  - #75                  - #80        - - Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                      85  - #                90  - #                95               - - Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Ar - #g Thr Val Ala Ala Pro                  100      - #           105      - #           110                  - -  - - (2) INFORMATION FOR SEQ ID NO:104:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 318 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...318                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                             - - CAG ATA GTA CTC TCC CAG TCT CCA GCA ATC CT - #G TCT GCA TCT CCA GGG           48                                                                       Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Le - #u Ser Ala Ser Pro Gly            1               5  - #                10  - #                15               - - GAG AAG GTC ACA ATG ACT TGC AGG GCC AGC TC - #A AGT GTA AAT TAC ATG           96                                                                       Glu Lys Val Thr Met Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                       20      - #            25      - #            30                   - - CAC TGG TAC CAG CAG AAG CCA GGA TCC TCC CC - #C AAA CCC TGG ATT TAT          144                                                                       His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pr - #o Lys Pro Trp Ile Tyr                   35          - #        40          - #        45                       - - GCC ACA TCC AAC CTG GCT TCT GGA GTC CCT GC - #T CGC TTC AGT GGC AGT          192                                                                       Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser               50              - #    55              - #    60                           - - GGG TCT GGG ACC TCT TAC TCT CTC ACA ATC AG - #C AGA GTG GAG GCT GAA          240                                                                       Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Se - #r Arg Val Glu Ala Glu           65                  - #70                  - #75                  - #80        - - GAT GCT GCC ACT TAT TAC TGC CAG CAG TGG AG - #T ATT AAC CCA CGG ACG          288                                                                       Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                           85  - #                90  - #                95               - - TTC GGT GGA GGC ACC AAG CTG GAA ATC AAA  - #                  - #              318                                                                     Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys                                                   100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:105:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 106 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                             - - Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Le - #u Ser Ala Ser Pro Gly       1               5  - #                10  - #                15               - - Glu Lys Val Thr Met Thr Cys Arg Ala Ser Se - #r Ser Val Asn Tyr Met                  20      - #            25      - #            30                   - - His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pr - #o Lys Pro Trp Ile Tyr              35          - #        40          - #        45                       - - Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Al - #a Arg Phe Ser Gly Ser          50              - #    55              - #    60                           - - Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Se - #r Arg Val Glu Ala Glu      65                  - #70                  - #75                  - #80        - - Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Se - #r Ile Asn Pro Arg Thr                      85  - #                90  - #                95               - - Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys                                              100      - #           105                                         - -  - - (2) INFORMATION FOR SEQ ID NO:106:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                             - - CAGATCCAAC TAGTGCAGTC TGGACCTGAG         - #                  - #               30                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:107:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 32 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                             - - TTAAGCTTGC TAGCTGCAGA GACAGTGACC AG       - #                  - #              32                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:108:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 369 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...369                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                             - - CAG ATC CAA CTA GTG CAG TCT GGA CCT GAG CT - #G AAG AAG CCT GGA GAG           48                                                                       Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Le - #u Lys Lys Pro Gly Glu            1               5  - #                10  - #                15               - - ACA GTC AAG ATC TCC TGC AAG GCT TCT GGG TA - #C ACC TTC ACA AAC TAT           96                                                                       Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                       20      - #            25      - #            30                   - - GGA ATG AAC TGG GTG AAG CAG GCT CCA GGA AA - #G GGT TTA AAG TGG ATG          144                                                                       Gly Met Asn Trp Val Lys Gln Ala Pro Gly Ly - #s Gly Leu Lys Trp Met                   35          - #        40          - #        45                       - - GGC TGG ATA AAC ACC AGA AAT GGA AAG TCA AC - #A TAT GTT GAT GAC TTC          192                                                                       Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe               50              - #    55              - #    60                           - - AAG GGA CGG TTT GCC TTC TCT TTG GAA AGC TC - #T GCC AGC ACT GCC AAT          240                                                                       Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Se - #r Ala Ser Thr Ala Asn           65                  - #70                  - #75                  - #80        - - TTG CAG ATC GAC AAC CTC AAA GAT GAG GAC AC - #G GCT ACA TAT TTC TGT          288                                                                       Leu Gln Ile Asp Asn Leu Lys Asp Glu Asp Th - #r Ala Thr Tyr Phe Cys                           85  - #                90  - #                95               - - ACA AGA GAA GGG AAT ATG GAT GGT TAC TTC CC - #T TTT ACT TAC TGG GGC          336                                                                       Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                       100      - #           105      - #           110                  - - CAA GGG ACT CTG GTC ACT GTC TCT GCA GCT AG - #C                  -      #        369                                                                    Gln Gly Thr Leu Val Thr Val Ser Ala Ala Se - #r                                       115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:109:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 123 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                             - - Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Le - #u Lys Lys Pro Gly        Glu                                                                              1               5  - #                10  - #                15              - - Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                  20      - #            25      - #            30                   - - Gly Met Asn Trp Val Lys Gln Ala Pro Gly Ly - #s Gly Leu Lys Trp Met              35          - #        40          - #        45                       - - Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe          50              - #    55              - #    60                           - - Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Se - #r Ala Ser Thr Ala Asn      65                  - #70                  - #75                  - #80        - - Leu Gln Ile Asp Asn Leu Lys Asp Glu Asp Th - #r Ala Thr Tyr Phe Cys                      85  - #                90  - #                95               - - Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                  100      - #           105      - #           110                  - - Gln Gly Thr Leu Val Thr Val Ser Ala Ala Se - #r                                  115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:110:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 363 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE:                                                   - -     (vi) ORIGINAL SOURCE:                                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Coding Se - #quence                                             (B) LOCATION: 1...363                                                         (D) OTHER INFORMATION:                                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                             - - CAG ATC CAA CTA GTG CAG TCT GGA CCT GAG CT - #G AAG AAG CCT GGA GAG           48                                                                       Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Le - #u Lys Lys Pro Gly Glu            1               5  - #                10  - #                15               - - ACA GTC AAG ATC TCC TGC AAG GCT TCT GGG TA - #C ACC TTC ACA AAC TAT           96                                                                       Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                       20      - #            25      - #            30                   - - GGA ATG AAC TGG GTG AAG CAG GCT CCA GGA AA - #G GGT TTA AAG TGG ATG          144                                                                       Gly Met Asn Trp Val Lys Gln Ala Pro Gly Ly - #s Gly Leu Lys Trp Met                   35          - #        40          - #        45                       - - GGC TGG ATA AAC ACC AGA AAT GGA AAG TCA AC - #A TAT GTT GAT GAC TTC          192                                                                       Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe               50              - #    55              - #    60                           - - AAG GGA CGG TTT GCC TTC TCT TTG GAA AGC TC - #T GCC AGC ACT GCC AAT          240                                                                       Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Se - #r Ala Ser Thr Ala Asn           65                  - #70                  - #75                  - #80        - - TTG CAG ATC GAC AAC CTC AAA GAT GAG GAC AC - #G GCT ACA TAT TTC TGT          288                                                                       Leu Gln Ile Asp Asn Leu Lys Asp Glu Asp Th - #r Ala Thr Tyr Phe Cys                           85  - #                90  - #                95               - - ACA AGA GAA GGG AAT ATG GAT GGT TAC TTC CC - #T TTT ACT TAC TGG GGC          336                                                                       Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                       100      - #           105      - #           110                  - - CAA GGG ACT CTG GTC ACT GTC TCT GCA    - #                  - #                363                                                                     Gln Gly Thr Leu Val Thr Val Ser Ala                                                   115          - #       120                                             - -  - - (2) INFORMATION FOR SEQ ID NO:111:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 121 amino - #acids                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -    (iii) HYPOTHETICAL: NO                                                 - -     (iv) ANTI-SENSE: NO                                                   - -      (v) FRAGMENT TYPE: internal                                          - -     (vi) ORIGINAL SOURCE:                                                 - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                             - - Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Le - #u Lys Lys Pro Gly Glu       1               5  - #                10  - #                15               - - Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Ty - #r Thr Phe Thr Asn Tyr                  20      - #            25      - #            30                   - - Gly Met Asn Trp Val Lys Gln Ala Pro Gly Ly - #s Gly Leu Lys Trp Met              35          - #        40          - #        45                       - - Gly Trp Ile Asn Thr Arg Asn Gly Lys Ser Th - #r Tyr Val Asp Asp Phe          50              - #    55              - #    60                           - - Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Se - #r Ala Ser Thr Ala Asn      65                  - #70                  - #75                  - #80        - - Leu Gln Ile Asp Asn Leu Lys Asp Glu Asp Th - #r Ala Thr Tyr Phe Cys                      85  - #                90  - #                95               - - Thr Arg Glu Gly Asn Met Asp Gly Tyr Phe Pr - #o Phe Thr Tyr Trp Gly                  100      - #           105      - #           110                  - - Gln Gly Thr Leu Val Thr Val Ser Ala                                              115          - #       120                                           __________________________________________________________________________

We claim:
 1. An isolated nucleic acid molecule encoding theimmunoglobulin complementarity determining region shown in SEQ ID NOs:9or
 10. 2. An isolated nucleic acid molecule encoding the immunoglobulincomplementarity determining region shown in SEQ ID NOs:12 or
 14. 3. Anisolated nucleic acid molecule encoding SEQ ID NO:52 or functionalfragments thereof.
 4. An isolated nucleic acid molecule encoding SEQ IDNO:74 or functional fragments thereof.
 5. An isolated nucleic acidmolecule encoding SEQ ID NOs:31, 44, 52, 57, 62, 74, 78, 89 or 99 orfunctional fragments thereof.
 6. An isolated nucleic acid moleculeencoding the immunoglobulin complementarity determining regions havingthe amino acid sequences shown in SEQ ID NOs: 8, 9 and
 10. 7. Anisolated nucleic acid molecule encoding the immunoglobulincomplementarity determining regions having the amino acid sequencesshown in SEQ ID NOs: 12, 13 and 14.